Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

ABSTRACT

The invention provides methods for the synthesis of a halichondrin macrolides through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic macrolide. The invention also provides compounds useful as intermediates in the synthesis of a halichondrin macrolides and methods for preparing the same.

BACKGROUND

The invention relates to intermediates useful in the synthesis ofpharmaceutically active macrolide compounds and methods of synthesizingmacrolide compounds. Halichondrin B is a potent anticancer agentoriginally isolated from the marine sponge Halichondria okadai, andsubsequently found in Axinella sp., Phakellia carteri, and Lissodendoryxsp. A total synthesis of halichondrin B was published in 1992 (Aicher,T. D. et al., J. Am. Chem. Soc. 114:3162-3164). Further synthetic andstructure-activity relationship studies have been discloses in U.S. Pat.Nos. 5,338,865 and 5,436,238 and in Towle et al., Annual Meeting of theAmerican Association for Cancer Research, Apr. 6-10, 2002, 5721 and Wanget al., Bioorg. Med. Chem. Lett., 10:1029-1032, 2000. Methods andintermediates for the synthesis of certain halichondrin B analogs andintermediates are described in International Publication Nos. WO2005/118565, WO 2009/046308, WO 2009/064029, and WO 2009/124237; U.S.Pat. No. 6,214,865; Austad et al., Synlett 24(3):333-337, 2013; Austadet al., Synlett. 24(3):327-332, 2013; and Chase et al., Synlett24(3):323-326, 2013. New methods for the synthesis of halichondrin B andits analogs (e.g., macrolide analogs) are desirable.

SUMMARY OF THE INVENTION

In general, the present invention provides methods for macrocyclizationof intermediates in the synthesis of a halichondrin macrolide. Theinvention also provides intermediates that can be employed in themacrocyclization reactions described herein.

In a first aspect, the invention provides a method of preparing amacrocyclic intermediate in the synthesis of a halichondrin macrolide,the method involving performing a macrocyclization reaction on anon-macrocyclic intermediate, the macrocyclization reaction producingthe macrocyclic intermediate by forming C.2-C.3, C.3-C.4, C.12-C.13,C.15-C.16, C.19-C.20, or C.26-C.27 bond in the structure of thehalichondrin macrolide.

In some embodiments of the first aspect, performing the macrocyclizationreaction involves contacting the non-macrocyclic intermediate (e.g., acompound of formula (IA)) with an organic base (e.g., DBU ortriethylamine) and a Lewis acid (e.g., a salt of Li or Zn). Thenon-macrocyclic intermediate can be a compound of formula (IA):

-   -   or a salt or a tautomer thereof,    -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group; and

the macrocyclic intermediate in the synthesis of a halichondrinmacrolide is a compound of formula (IB):

-   -   or a salt or a tautomer thereof.

In formula (IA) or (IB), each R can be optionally substituted C₁₋₆alkyl. In formula (IA) or (IB), both P₄ groups and X₁, together with theatoms to which each is attached, can combine to form ketal. In formula(IA) or (IB), X₁, together with the carbon atom to which it is attached,can be —(CH(OP_(Y)))—, where P_(Y) is H or a hydroxyl protecting group.In formula (IA) or (IB), P₅ can be a hydroxyl protecting group. Informula (IA) or (IB), R₃ and R₄ can combine to form a bond, and R₅ canbe H.

In particular embodiments of the first aspect, performing themacrocyclization reaction involves contacting the non-macrocyclicintermediate (e.g., a compound of formula (IIA), formula (IIIA), formula(IVA), or formula (VA)) with an olefin metathesis catalyst (e.g., aruthenium-carbene complex).

The non-macrocyclic intermediate can be a compound of formula (IIA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group; and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (IB):

-   -   or a salt or a tautomer thereof.

The non-macrocyclic intermediate can be a compound of formula (IIIA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl; each Q₁ is independently        OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A), NR_(B)R_(A),        NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A), NR_(A)(CO)NR_(B)R_(A),        NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A), (CO)NR_(B)R_(A), or        O(CO)NR_(B)R_(A), where each of R_(A) and R_(B) is independently        H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl,        hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,        alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or        heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group; and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (IIIB):

-   -   or a salt or a tautomer thereof.

In formula (IIA), (IIB), (IIIA), or (IIIB), both P₄ groups and X₁,together with the atoms to which each is attached, can combine to formketal. In formula (IIA), (IIB), (IIIA), or (IIIB), P₅ can be a hydroxylprotecting group. In formula (IIA), (IIB), (IIIA), or (IIIB), X₁,together with the carbon atom to which it is attached, can be—(CH(OP_(Y)))—, where P_(Y) is H. In formula (IIA), (IIB), (IIIA), or(IIIB), X₁ can be oxo.

the non-macrocyclic intermediate is a compound of formula (IVA):

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (i) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;

    -   (ii) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;

    -   or

    -   (iii) R₃ and R₄ combine to form a bond, and R₅ is H;

    -   each P₄ and P₅ is independently H or a hydroxyl protecting        group;

    -   R₆ is H, and P₆ is H or a hydroxyl protecting group; or R₆ and        P₆ combine to form a double bond; and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (IVB):

-   -   or a salt thereof.

In formula (IVA) or (IVB), at least one of P₄ and P₅ can be H. Informula (IVA) or (IVB), R₆ and P₆ can combine to form a double bond.

The non-macrocyclic intermediate can be a compound of formula (VA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;

    -   (a2) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;

    -   or

    -   (a3) R₃ and R₄ combine to form a bond, and R₅ is H;

    -   (b1) A₁ and R₇ combine to form oxo, R₆ is H or a hydroxyl        protecting group, and R₈ is H;

    -   or

    -   (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting        group, and:        -   (i) R₆ is H or a hydroxyl protecting group, and R₇ and R₈            combine to form a double bond;        -   or        -   (ii) R₆ and R₇ combine to form a bond, and R₈ is H or OP″;

    -   (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;

    -   or

    -   (c2) R₉ and P₄ combine to form a double bond;

    -   R₁₀ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₁₁)₂—, or NP₆,        and where each R₁₁ is independently H or —COOR₁₂, P₆ is an        N-protecting group, and R₁₂ is alkyl;

    -   each P₅ is independently H or a hydroxyl protecting group; and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (VB):

-   -   or a salt or a tautomer thereof.

In formula (VA) or (VB), R₉ can be H, and P₄ can be H. In formula (VA)or (VB), R₁₀ can be —CH₂X₁CH₂CH═CH₂, and X₁ can be O. In formula (VA) or(VB), R₆ and R₇ can combine to form a bond, and R₈ can be H. In formula(VA) or (VB), each P₅ can be independently a hydroxyl protecting group.In formula (VA) or (VB), at least one P₅ can be H. In formula (VA) or(VB), R₃ and R₄ can combine to form a bond, and R₅ can be H.

In certain embodiments of the first aspect, performing themacrocyclization reaction involves contacting the non-macrocyclicintermediate (e.g., a compound of formula (VIA) or (VIIA)) with a Cr(II)salt and a Ni(II) salt.

The non-macrocyclic intermediate can be a compound of formula (VIA):

-   -   or a salt or a tautomer thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   b designates (R)-stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or b designates (S)-stereogenic        center, and Z is OR₆, where R₆ is a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo; or both P₄ groups and X₁, together with the atoms to        which each is attached, combine to form ketal; and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (IVB):

-   -   or a salt or a tautomer thereof,    -   where        -   b designates (R)-stereogenic center, c designates            (S)-stereogenic center, and Z is a sulfonate, chloride,            bromide, or iodide;        -   or        -   b designates (S)-stereogenic center, c designates            (R)-stereogenic center, and Z is OR₆, where R₆ is a hydroxyl            protecting group.

In formula (VIA) or (VIB), Y can be bromide. In formula (VIA) or (VIB),R₃ and R₄ can combine to form a bond, and R₅ can be H. In formula (VIA)or (VIB), both P₄ groups and X₁, together with the atoms to which eachis attached, can combine to form ketal. In formula (VIA) or (VIB), Z canbe a sulfonate. In formula (VIA) or (VIB), Z can be OR₆, where R₆ is ahydroxyl protecting group. In formula (VIA) or (VIB), Z can be an ester,carbonate, or carbamate.

The non-macrocyclic intermediate can be a compound of formula (VIIA):

-   -   or a salt thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—, where R₈ is H or a        hydroxyl protecting group;

    -   or

    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;

    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;

    -   or

    -   (b2) Z and R₇ combine to form a double bond, and R₆ is a        hydroxyl protecting group;

    -   and

    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (VIIB):

-   -   or a salt thereof,    -   where each of P₅ and R₆ is independently H or a hydroxyl        protecting group.

In formula (VIIA), Z can be iodide. In formula (VIIA) or (VIIB), Y canbe trifluoromethanesulfonate. In formula (VIIA) or (VIIB), R₃ can be Hor a hydroxyl protecting group, R₄ and R₅ can combine to form a doublebond, each P₄ can independently be H or a hydroxyl protecting group, andX₁, together with the carbon to which it is attached, can form—(CH(OR₈))—, where R₈ is H or a hydroxyl protecting group. In formula(VIIA) or (VIIB), at least one of P₃, P₄, and R₆ can be a hydroxylprotecting group. In formula (VIIA), Z can be chloride, bromide, oriodide, and R₆ and R₇ combine to form a bond.

In a second aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond; R₂ is H or            —(CH₂)_(n)OP₃, and each of P₂ and P₃ is independently H,            optionally substituted alkyl, or a hydroxyl protecting            group, or P₂ and P₃, together with the atoms to which each            is attached, combine to form a ketal, a cyclic carbonate, a            dicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to            form an optionally substituted ethylene or a structure            selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (IB) from a compound of        formula (IA), the compound of formula (IA) having the following        structure:

-   -   or a salt or a tautomer thereof,    -   wherein    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and    -   P₅ is H or a hydroxyl protecting group; and    -   the compound of formula (IB) having the following structure:

-   -   or a salt or a tautomer thereof;    -   and    -   (B) producing the halichondrin macrolide from compound (IB).

In some embodiments of the second aspect, the producing the compound offormula (IB) involves reacting the compound of formula (IA) with anorganic base and a Lewis acid. In certain embodiments of the secondaspect, the producing the halichondrin macrolide involves reacting thecompound of formula (IB) with a hydroxyl protecting group removingagent. In particular embodiments of the second aspect, each R isoptionally substituted alkyl.

In a third aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (IB) from a compound of        formula (IIA), the compound of formula (IIA) having the        following structure:

-   -   or a salt or a tautomer thereof,    -   wherein        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and    -   P₅ is H or a hydroxyl protecting group; and    -   the compound of formula (IB) having the following structure:

-   -   or a salt or a tautomer thereof;    -   and    -   (B) producing the halichondrin macrolide from compound (IB).

In some embodiments of the third aspect, the producing the compound offormula (IB) involves reacting the compound of formula (IIA) with anolefin metathesis catalyst (e.g., a ruthenium-carbene complex). In someembodiments of the third aspect, the producing the halichondrinmacrolide involves reacting the compound of formula (IB) with a hydroxylprotecting group removing agent.

In a fourth aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   wherein    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (IIIB) from a compound of        formula (IIIA), the compound of formula (IIIA) having the        following structure:

-   -   or a salt or a tautomer thereof,    -   wherein        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and    -   P₅ is H or a hydroxyl protecting group; and    -   the compound of formula (IIIB) having the following structure:

-   -   or a salt or a tautomer thereof;    -   and    -   (B) producing the halichondrin macrolide from the compound of        formula (IIIB).

In some embodiments of the fourth aspect, the producing the compound offormula (IIIB) involves reacting the compound of formula (IIIA) with anolefin metathesis catalyst. In certain embodiments of the fourth aspect,the producing the halichondrin macrolide involves reacting the compoundof formula (IIIB) with a hydroxyl protecting group removing agent. Inparticular embodiments of the fourth aspect, both P₄ groups and X₁,together with the atoms to which each is attached, combine to formketal. In further embodiments of the fourth aspect, P₅ is a hydroxylprotecting group.

In a fifth aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (IVB) from a compound of        formula (IVA), the compound of formula (IVA) having the        following structure:

-   -   or a salt thereof,    -   where    -   (i) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;    -   (ii) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond; or    -   (iii) R₃ and R₄ combine to form a bond, and R₅ is H;    -   each P₄ and P₅ is independently H or a hydroxyl protecting        group;    -   R₆ is H, and P₆ is H or a hydroxyl protecting group; or R₆ and        P₆ combine to form a double bond; and    -   the compound of formula (IVB) having the following structure:

-   -   or a salt thereof;    -   and    -   (B) producing the halichondrin macrolide from the compound of        formula (IVB).

In some embodiments of the fifth aspect, the producing the compound offormula (IVB) involves reacting the compound of formula (IVA) with anolefin metathesis catalyst. In certain embodiments of the fifth aspect,the producing the halichondrin macrolide from the compound of formula(IVB) involves reacting the compound of formula (IVB) with a Brønstedacid. In other embodiments of the fifth aspect, the producing thehalichondrin macrolide involves producing the compound of formula (IVC),the compound of formula (IVC) having the following structure:

-   -   or a salt thereof;    -   and producing the halichondrin macrolide from the compound of        formula (IVC).

In yet other embodiments of the fifth aspect, the producing the compoundof formula (IVC) involves reacting the compound of formula (IVB) with ahydroxyl protecting group removing agent. In still other embodiments ofthe fifth aspect, the producing the halichondrin macrolide from thecompound of formula (IVC) involves reacting the compound of formula(IVC) with a Brønsted acid. In particular embodiments of the fifthaspect, at least one of P₄ and P₅ is H.

In a sixth aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (VB) from a compound of        formula (VA), the compound of formula (VA) having the following        structure:

-   -   or a salt or a tautomer thereof,    -   where    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;    -   (a2) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;    -   or    -   (a3) R₃ and R₄ combine to form a bond, and R₅ is H;    -   (b1) A₁ and R₇ combine to form oxo, R₆ is H or a hydroxyl        protecting group, and R₈ is H;    -   or    -   (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting        group, and:        -   (i) R₆ is H or a hydroxyl protecting group, and R₇ and R₈            combine to form a double bond;        -   or        -   (ii) R₆ and R₇ combine to form a bond, and R₈ is H or OP″;    -   (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₉ and P₄ combine to form a double bond;    -   R₁₀ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₁₁)₂—, or NP₆,        and where each R₁₁ is independently H or —COOR₁₂, P₆ is an        N-protecting group, and R₁₂ is alkyl;    -   each P₅ is independently H or a hydroxyl protecting group; and    -   where the macrocyclic intermediate in the synthesis of a        halichondrin macrolide is a compound of formula (VB):

-   -   or a salt or a tautomer thereof;    -   (B) producing a compound of formula (VC) from the compound of        formula (VB), the compound of formula (VC) having the following        structure:

-   -   or a salt thereof,    -   where each of A₁ and A₂ is independently H or OP″;    -   (C) producing a compound of formula (IVC) from the compound of        formula (VC), the compound of formula (IVC) having the following        structure:

-   -   or a salt thereof,    -   where each of A₁ and A₂ is independently H or OP″; and    -   (D) producing the halichondrin macrolide from the compound of        formula (IVC).

In some embodiments of the sixth aspect, the producing the compound offormula (VB) involves contacting the compound of formula (VA) with anolefin metathesis catalyst. In certain embodiments of the sixth aspect,P₄ is H, R₉ is H, and the producing the compound of formula (VC)involves oxidizing the compound of formula (VB) to produce a compound offormula (VBa):

-   -   or a salt thereof;    -   where each of A₁ and A₂ is independently H or OP″    -   and reacting the compound of formula (VBa) with a 1,4-reducing        agent to produce the compound of formula (VC).

In particular embodiments of the sixth aspect, the producing thecompound of formula (IVC) involves contacting the compound of formula(VC) with a hydroxyl protecting group removing agent. In furtherembodiments of the sixth aspect, the producing the halichondrinmacrolide involves contacting the compound of formula (IVC) with aBrønsted acid.

In a seventh aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (VIB) from a compound of        formula (VIA), the compound of formula (VIA) having the        following structure:

-   -   or a salt or a tautomer thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   b designates (R)-stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or b designates (S)-stereogenic        center, and Z is OR₆, where R₆ is a hydroxyl protecting group;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo; or both P₄ groups and X₁, together with the atoms to        which each is attached, combine to form ketal;    -   the compound of formula (VIB) having the following structure:

-   -   or a salt or a tautomer thereof,    -   where        -   b designates (R)-stereogenic center, c designates            (S)-stereogenic center, and Z is a sulfonate, chloride,            bromide, or iodide;        -   or        -   b designates (S)-stereogenic center, c designates            (R)-stereogenic center, and Z is OR₆, where R₆ is a hydroxyl            protecting group;    -   (B) producing the halichondrin macrolide from the compound of        formula (VIB).

In some embodiments of the seventh aspect, the producing the compound offormula (VIB) involves reacting the compound of formula (VIA) with aCr(II) salt and a Ni(II) salt. In particular embodiments of the seventhaspect, the producing the halichondrin macrolide involves the step ofnucleophilic ring-closing of the compound of formula (VIB). In certainembodiments of the seventh aspect, both P₄ groups and X₁, together withthe atoms to which each is attached, combine to form ketal. In furtherembodiments of the seventh aspect, R₃ and R₄ combine to form a bond, andR₅ is H.

In an eighth aspect, the invention provides a method of preparing:

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   the method involving:

    -   (A) producing a compound of formula (VIIB) from a compound of        formula (VIIA), the compound of formula (VIIA) having the        following structure:

-   -   or a salt thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;    -   or    -   (b2) Z and R₇ combine to form a double bond, and R₆ is a        hydroxyl protecting group;    -   and    -   where R₈ is H or a hydroxyl protecting group;    -   and    -   the compound of formula (VIIB) having the following structure:

-   -   or a salt thereof,    -   where each of P₅ and R₆ is independently H or a hydroxyl        protecting group;    -   (B) producing a compound of formula (VIIC) from the compound of        formula (VIIB), the compound of formula (VIIC) having the        following structure:

-   -   or a salt or a tautomer thereof,    -   where        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;    -   (C) producing a compound of formula (VIID) from the compound of        formula (VIIC), the compound of formula (VIID) having the        following structure:

-   -   or a salt thereof,    -   where each of A₁ and A₂ is independently H or OP″;    -   and    -   (D) producing the halichondrin macrolide from the compound of        formula (VIID).

In some embodiments of the eighth aspect, the producing the compound offormula (VIIB) involves reacting the compound of formula (VIIA) with aCr(II) salt and a Ni(II) salt. In certain embodiments of the eighthaspect, the producing the compound of formula (VIIC) involves the stepof nucleophilic ring-closing of the compound of formula (VIIB). Inparticular embodiments of the eighth aspect, the producing the compoundof formula (VIID) involves reacting the compound of formula (VIIC) witha hydroxyl protecting group removing agent. In further embodiments ofthe eighth aspect, the producing the halichondrin macrolide involvesreacting the compound of formula (VIID) with a Brønsted acid. In otherembodiments of the eighth aspect, Z is iodide. In yet other embodimentsof the eighth aspect, Y is trifluoromethanesulfonate. In stillembodiments of the eighth aspect, R₃ is H or a hydroxyl protectinggroup, and R₄ and R₅ combine to form a double bond. In some embodimentsof the eighth aspect, each P₄ is independently H or a hydroxylprotecting group, and X₁, together with the carbon to which it isattached, forms —(CH(OR₈))—, where R₈ is H or a hydroxyl protectinggroup. In particular embodiments of the eighth aspect, P₅ is H. Incertain embodiments of the eighth aspect, Z is chloride, bromide, oriodide, and R₆ and R₇ combine to form a bond.

In some embodiments of any aspect, a designates (S)-stereogenic center.In certain embodiments of any aspect, one and only one of D and D′ isoptionally substituted alkyl or OP₁. In particular embodiments of anyaspect, one and only one of D and D′ is OP₁, where P₁ is H, alkyl, or ahydroxyl protecting group. In further embodiments of any aspect, A is agroup of formula (1). In certain embodiments of any aspect, L is—(CH(OP₂))—. In other embodiments of any aspect, R₁ and P₁ combine toform a bond. In yet other embodiments of any aspect, G is O. In stillother embodiments of any aspect, E is optionally substituted alkyl. Insome embodiments of any aspect, k is 1. In certain embodiments of anyaspect, R₂ is —(CH₂)_(n)OP₃. In particular embodiments of any aspect, atleast one of P₂ and P₃ is a hydroxyl protecting group. In certainembodiments of any aspect, A₁ is H. In some embodiments of any aspect,A₂ is H.

In a ninth aspect, the invention provides a method of preparing anintermediate in the synthesis of a halichondrin macrolide. The methodinvolves performing an allene-Prins reaction by contacting a compound offormula (VIIIA) with a compound of formula (VIIIB) and R₄OH,

-   -   where R₄ is an optionally substituted acyl;    -   where the compound of formula (VIIIA) has the following        structure:

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of    -   D and D′ is OP₁, where P₁ is H, alkyl, or a hydroxyl protecting        group; A is a group of formula (1) or a C₁₋₆ saturated or C₂₋₆        unsaturated hydrocarbon skeleton, the skeleton being        unsubstituted or having from 1 to 10 substituents independently        selected from the group consisting of cyano, halo, azido, oxo,        and Q₁, the group of formula (1) having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   X is O, or X, together with the carbon atom to which it is        attached, forms —(C(OP_(z))₂)—, wherein each P_(z) is        independently optionally substituted alkyl or optionally        substituted aryl, or both P_(z) combine to form optionally        substituted alkylene or optionally substituted arylene; and

    -   P₄ is H or a hydroxyl protecting group;

    -   where the compound of formula (VIIIB) has the following        structure:

-   -   where    -   R₃ is —CH₂—OP₅, —CH═CH₂,

-   -   where P₅ is H or a hydroxyl protecting group; each P₆ is        independently a hydroxyl protecting group, or both P₆ groups,        together with the atoms to which each is attached, combine to        form a cyclic protected diol; and R₅ is H or —CH₂X₁CH₂CH═CH₂,        where X₁ is O, —CH₂—, or NP₇, where P₇ is a sulfonyl;    -   and where the intermediate is a compound of formula (VIIIC):

-   -   or a salt thereof,    -   where a designates (R)-stereogenic center or (S)-stereogenic        center.

In some embodiments of the ninth aspect, the performing a Prins reactioninvolves reacting the compound of formula (VIIIA) with a Lewis acid. Incertain embodiments of the ninth aspect, k is 1.

In a tenth aspect, the invention provides a compound of formula (IA) orformula (IB),

-   -   or a salt or a tautomer thereof,    -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group.

In an eleventh aspect, the invention provides a compound of formula(IIA), formula (IIA), or formula (IIIB):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group.

In a twelfth aspect, the invention provides a compound of formula (IVA),formula (IVB), or formula (IVC):

-   -   or a salt thereof,    -   where    -   each of A₁ and A₂ is H or OP″, where P″ is H or a hydroxyl        protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (i) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;

    -   (ii) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;

    -   or

    -   (iii) R₃ and R₄ combine to form a bond, and R₅ is H;

    -   each P₄ and P₅ is independently H or a hydroxyl protecting        group; and

    -   R₆ is H, and P₆ is H or a hydroxyl protecting group; or R₆ and        P₆ combine to form a double bond.

In a thirteenth aspect, the invention provides a compound of formula(VA), formula (VB), or formula (VC):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;

    -   (a2) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;

    -   or

    -   (a3) R₃ and R₄ combine to form a bond, and R₅ is H;

    -   (b1) A₁ and R₇ combine to form oxo, R₆ is H or a hydroxyl        protecting group, and R₈ is H;

    -   or

    -   (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting        group, and:        -   (i) R₆ is H or a hydroxyl protecting group, and R₇ and R₈            combine to form a double bond;        -   or        -   (ii) R₆ and R₇ combine to form a bond, and R₈ is H or OP″;

    -   (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;

    -   or

    -   (c2) R₉ and P₄ combine to form a double bond;

    -   R₁₀ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₁₁)₂—, or NP₆,        and where each R₁₁ is independently H or —COOR₁₂, P₆ is an        N-protecting group, and R₁₂ is alkyl;

    -   each P₅ is independently H or a hydroxyl protecting group; and

In a fourteenth aspect, the invention provides a compound of formula(VIA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   Y is iodide, bromide, or trifluoromethanesulfonate;

    -   b designates (R)-stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or b designates (S)-stereogenic        center, and Z is OR₆, where R₆ is a hydroxyl protecting group;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:        -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅            combine to form a double bond;        -   or        -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal.

In a fifteenth aspect, the invention provides a compound of formula(VIB):

-   -   or a salt or a tautomer thereof,    -   where        -   b designates (R)-stereogenic center, c designates            (S)-stereogenic center, and Z is a sulfonate, chloride,            bromide, or iodide;        -   or        -   b designates (S)-stereogenic center, c designates            (R)-stereogenic center, and Z is OR₆, where R₆ is a hydroxyl            protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal.

In a sixteenth aspect, the invention provides a compound of formula(VIIA) or formula (VIIB):

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—;

    -   or

    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;

    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;

    -   (b2) Z and R₇ combine to form a double bond, and R₆ is a        hydroxyl protecting group;

    -   or

    -   (b3) when Z and R₇ are absent, R₆ is H or a hydroxyl protecting        group;

    -   P₅ is H or a hydroxyl protecting group;

    -   where R₈ is H or a hydroxyl protecting group.

In a seventeenth aspect, the invention provides a compound of formula(VIIC):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   each P₄ is H or a hydroxyl protecting group, and X₁ is oxo or        X₁, together with the carbon atom to which it is attached, is        —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting        group; or both P₄ groups and X₁, together with the atoms to        which each is attached, combine to form a ketal; and        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;            -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″.

In an eighteenth aspect, the invention provides a compound of formula(VIIIC):

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -   where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   P₄ is H or a hydroxyl protecting group; and

    -   R₃ is —CH₂—OP₅, —CH═CH₂,

-   -   -   where P₅ is H or a hydroxyl protecting group; each P₆ is            independently a hydroxyl protecting group, or both P₆            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; and R₅ is H or            —CH₂X₁CH₂CH═CH₂, where X₁ is O, —CH₂—, or NP₇, where P₇ is a            sulfonyl.

The invention also features compounds of formula (IA), (IB), (IC), (IE),(IF), (IIA), (IIB), (IIC), (IICa), (IIIA), (IIIB), (IVA), (IVB), (IVC),(IVD), (IVE), (VA), (VB), (VBa), (VC), (VIA), (VIB), (VIC), (VIIA),(VIIB), (VIIC), (VIID), (VIIE), (VIIF), (VIIG), (VIIIA), (VIIIB),(VIIIC), or (VIIID).

In certain embodiments of formula (IA), (IB), (IC), (IIA), (IIB),(IIIA), (IIIB), (VIA), (VIB), (VIC), (VIIA), (VIIB), and/or (VIIC) ofthe above aspects, each P₄ is independently H or a hydroxyl protectinggroup, and X₁ is oxo; or both P₄ groups and X₁, together with the atomsto which each is attached, combine to form ketal (e.g., each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo).

In particular embodiments of formula (VIIIA) of the above aspects, X isO or X, together with the carbon to which it is attached, forms anacetal (e.g., cyclic acetal).

Definitions

Compounds useful in the invention may be isotopically labeled compounds.Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g.,²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, and ¹⁷O). Isotopically-labeled compounds canbe prepared by synthesizing a compound using a readily availableisotopically-labeled reagent in place of a non-isotopically-labeledreagent.

For any of the following chemical definitions, a number following anatomic symbol indicates that total number of atoms of that element thatare present in a particular chemical moiety. As will be understood,other atoms, such as hydrogen atoms, or substituent groups, as describedherein, may be present, as necessary, to satisfy the valences of theatoms. For example, an unsubstituted C₂ alkyl group has the formula—CH₂CH₃. When used with the groups defined herein, a reference to thenumber of carbon atoms includes the divalent carbon in acetal and ketalgroups but does not include the carbonyl carbon in acyl, ester,carbonate, or carbamate groups. A reference to the number of oxygen,nitrogen, or sulfur atoms in a heteroaryl group only includes thoseatoms that form a part of a heterocyclic ring.

By “acetal” is meant —O—(CHR)—O—, where R is H, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl,optionally substituted arylalkyl, or a bond to the chain of carbon atomswithin an intermediate in the synthesis of the halichondrin macrolide.

By “acyl” is meant —C(O)R, where R is H, alkyl, alkenyl, aryl, orarylalkyl. In exemplary acyl groups, R is H, C₁₋₁₂ alkyl (e.g., C₁₋₈,C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈,C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀,C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., monocyclic C₁₋₄or C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl),(C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₁₋₆)heteroaryl(C₁₋₆)alkyl, or(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl grouppresent in an acyl group has from 1 to 4 heteroatoms selectedindependently from O, N, and S. An acyl group can be unsubstituted orsubstituted (e.g., optionally substituted acyl). In the optionallysubstituted acyl group, the substituent R is H, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl. In some embodiments, acyl is C₂₋₁₀acyl.

By “acylating agent” is meant a compound that reacts with an amine or ahydroxyl group to produce an amide or an ester, respectively. Anacylating agent has a formula R-LG, where R is acyl, and LG is halogen,carbonate, or —OR′, where R′ is acyl.

By “alkoxide” is meant an anionic compound RO⁻, where R is alkyl. Acounterion for alkoxide can be an alkali metal cation, an alkali earthmetal cation, or a tetraalkylammonium cation. Alkoxide can be optionallysubstituted in the same manner as alkyl.

By “alkoxy” is meant —OR, where R is alkyl. Alkoxy can be optionallysubstituted in the same manner as alkyl.

By “alkoxyalkyl” is meant —OR, where R is alkyl substituted by alkoxy.Each portion of the alkoxyalkyl can be optionally substituted in thesame manner as alkyl.

By “alkoxyaryl” is meant —R′(R″)_(n), where n is 1 or 2, R′ is aryleneand R″ is alkoxy, as defined herein. R′ can be further optionallysubstituted in the same manner as aryl. R″ can be optionally substitutedin the same manner as alkyl.

By “alkoxyarylalkyl” is meant —R′(R″(R′″)_(n)), where n is an integerfrom 1 to 3, R′ is alkylene, R″ is arylene, and R′″ is alkoxy, asdefined herein. R′ can be optionally substituted in the same manner asalkyl. R″ can be further optionally substituted in the same manner asaryl. R′″ can be optionally substituted in the same manner as alkyl.

By “alkyl” is meant a straight or branched chain saturated cyclic (i.e.,cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unlessotherwise specified. In some embodiments, alkyl is C₁₋₆ alkyl. Exemplaryalkyl groups include C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl.Specific examples include methyl, ethyl, 1-propyl, 2-propyl,2-methyl-1-propyl, 1-butyl, 2-butyl, and the like. Alkyl group can beoptionally substituted with 1, 2, 3, or 4 substituents selected from thegroup consisting of halogen, hydroxy, alkoxy, aryloxy, arylalkyloxy,amino, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino,[aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl,cyano, nitro, carboxyl, and azido.

By “alkylamino” is meant —NHR, where R is alkyl. By“[alkenyl]alkylamino” is meant —NRR′, where R is alkyl, and R′ isalkenyl. By “[aryl]alkylamino” is meant —NRR′, where R is alkyl, and R′is aryl. By “[arylalkyl]alkylamino” is meant —NRR′, where R is alkyl,and R′ is arylalkyl. By “dialkylamino” is meant —NR₂, where each R isalkyl, selected independently.

By “alkylaryl” is meant —R′(R″)_(n), where n is an integer from 1 to 3,R′ is arylene, and R″ is alkyl. Alkylaryl can be optionally substitutedin the same manner as defined for each R′ and R″ group.

By “alkylene” is meant a multivalent alkyl group. Alkylene groups can beoptionally substituted in the same manner as alkyl groups. For example,a C₁ alkylene group is —CH₂—.

By “alkylenedithio” is meant —S-alkylene-S—. Alkylenedithio can beoptionally substituted in the same manner as an alkylene group.

By “alkylhaloaryl” is meant —R′(R″)_(n)—R′″, where n is an integer from1 to 5 and R′ is arylene, R″ is halogen, and R′″ is alkylene, as definedherein. R′ can be further optionally substituted in the same manner asaryl. R′″ can be further optionally substituted in the same manner asalkyl.

By “alkylthio” is meant —SR, where R is alkyl. Alkylthio can beoptionally substituted in the same manner as an alkyl group.

By “alkenyl” is meant a straight or branched chain cyclic or acyclichydrocarbon group of, unless otherwise specified, from 2 to 12 carbonsand containing one or more carbon-carbon double bonds. In someembodiments, alkenyl is C₂₋₆ alkenyl. Exemplary alkenyl groups includeC₂₋₈, C₂₋₇, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl. Specific examplesinclude ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl),2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like.Alkenyl group can be optionally substituted in the same manner as alkylgroups. Alkenyl groups, used in any context herein, may also besubstituted with an aryl group.

By “amido” is meant —NHR, where R is acyl. Amido can be optionallysubstituted in the same manner as acyl.

By “aminal” is meant —O—CR₂—NR′—, where each R is independently H,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl, or both R groupsare together optionally substituted alkylene, and R′ is H or anN-protecting group. In particular, R′ can be an N-protecting group(e.g., Boc).

By “amino” is meant —NR₂, where N and R₂ combine to form azido, or eachR is independently H or an N-protecting group, or both R combine to forman N-protecting group. Amino can be unmasked, when each R is H, ormasked, when at least one R is not H. Thus, optionally masked amino canbe masked or unmasked amino.

By “aminoalkyl” is meant —R′(R″)_(n), where n is 1 or 2, R′ is alkylene,and R″ is amino, as defined herein. R′ can be optionally substituted inthe same manner as an alkyl group.

By “aryl” is meant a monocyclic or multicyclic ring system having one ormore aromatic rings, where the ring system is carbocyclic. Exemplaryaryl groups include C₆₋₂₀, C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl. Apreferred aryl group is a C₆₋₁₀ aryl group. Specific examples ofcarbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl,phenanthryl, anthracyl, and fluorenyl. Aryl group can be optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy,arylalkyloxy, alkylthio, alkylenedithio, alkylamino,[alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino,dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By “arylalkyl” is meant —R′R″, where R′ is alkylene, and R″ is aryl.Arylalkyl can be optionally substituted in the same manner as definedfor each R′ and R″ group.

By “arylalkyloxy” is meant —OR, where R is arylalkyl. Arylalkyloxy canbe optionally substituted in the same manner as defined for arylalkyl.

By “arylene” is meant a multivalent aryl group. Arylene groups can beoptionally substituted in the same manner as aryl groups. For example, aC₆ arylene group is phenylene.

By “aryloxy” is meant —OR, where R is aryl. Aryloxy can be optionallysubstituted in the same manner as aryl.

By “azido” is meant —N₃.

By “boronate” is meant —OBRO—, where R is alkyl, alkenyl, aryl,arylalkyl, alkoxy, or 2,6-diacetamidophenyl. Boronate can besubstituted, when R is a substituted alkyl, substituted alkenyl,substituted aryl, substituted arylalkyl, or substituted alkoxy.Alternatively, boronate can be unsubstituted, when R is unsubstitutedalkyl, unsubstituted alkenyl, aryl, unsubstituted arylalkyl,unsubstituted alkoxy, or 2,6-diacetamidophenyl.

By “carbamate” is meant a group, when a hydroxyl protecting group,having the formula —OC(O)NR₂, or, when an amine protecting group, havingthe formula —NR′—C(O)OR, where each R and R′ is independently H,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “carbonate” is meant —OC(O)OR, where R is optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl.

By “carbonyl” is meant —C(O)—.

By “carboxyl” is meant —C(O)OH, in free acid, ionized, or salt form.

By “carboxylic acid” is meant R—OH, where R is optionally substitutedacyl.

By “carboxylic acid anhydride” is meant R—O—R, where each R isindependently optionally substituted acyl.

By “cyclic carbonate” is meant —OC(O)O— that is part of a ring.

By “dicarbonyl” is meant —C(O)—C(O)—. Dicarbonyl-dioxo is —OC(O)—COO—.

By “ester” is meant —OC(O)R, where —C(O)R is an optionally substitutedacyl group.

By “ether” is meant —OR, where R is alkyl, alkenyl, arylalkyl, silyl, or2-tetrahydropyranyl. Ether can be optionally substituted as defined foreach R group.

By “halichondrin macrolide” is meant a lactone including the structureof carbons 1-30 as shown in Chart 1, wherein carbons 29 and 30 form partof a five- or six-membered ring.

By “haloalkyl” is meant —R′(R″)_(n), where n is an integer from 1 to 5and R′ is alkylene and R″ is halogen, as defined herein. R′ can befurther optionally substituted in the same manner as alkyl

By “haloaryl” is meant —R′(R″)_(n), where n is an integer from 1 to 5and R′ is arylene and R″ is halogen, as defined herein. R′ can befurther optionally substituted in the same manner as aryl.

By “haloarylalkyl” is meant —R′(R″(R′″)_(n)), where n is an integer from1 to 5 and R′ is alkylene, R″ is arylene, and R′″ is halogen, as definedherein. R′ can be further optionally substituted in the same manner asalkyl. R″ can be further optionally substituted in the same manner asaryl.

By “halogen” is meant fluoro, chloro, bromo, or iodo.

By “heterocyclic radical” is meant a 5-, 6- or 7-membered ring, unlessotherwise specified, containing one, two, three, or four heteroatomsindependently selected from the group containing nitrogen, oxygen, andsulfur. The 5-membered ring has zero to one double bonds, and the 6- and7-membered rings have zero to two double bonds. Certain heterocyclylgroups include from 1 to 9 carbon atoms. Other such groups may includeup to 12 carbon atoms. The term “heterocyclyl” also represents aheterocyclic compound having a bridged multicyclic structure in whichone or more carbons and/or heteroatoms bridges two non-adjacent membersof a monocyclic ring, e.g., a quinuclidinyl group. The term“heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups inwhich any of the above heterocyclic rings is fused to one, two, or threecarbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexenering, a cyclopentane ring, a cyclopentene ring, or another monocyclicheterocyclic ring, such as indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples offused heterocyclyls include tropanes and1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics include pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl,thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl,isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, purinyl,thiadiazolyl (e.g., 1,3,4-thiadiazole), tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl,dithiazolyl, benzofuranyl, benzothienyl and the like. Still otherexemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl;2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl(e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl);2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g.,2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl);2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g.,2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl);4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino5-oxo-1H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl);2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl);1,6-dihydro-6-oxopyridiminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g.,2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl);1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl);1,6-dihydro-6-oxo-pyridazinyl (e.g.,1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl(e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl);2,3-dihydro-2-oxo-1H-indolyl (e.g.,3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and2,3-dihydro-2-oxo-3,3′-spiropropane-1H-indol-1-yl);1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl;1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl);2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g.,3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl);2,3-dihydro-2-oxo-benzoxazolyl (e.g.,5-chloro-2,3-dihydro-2-oxo-benzoxazolyl);2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H-benzopyranyl;1,4-benzodioxanyl; 1,3-benzodioxanyl;2,3-dihydro-3-oxo,4H-1,3-benzothiazinyl;3,4-dihydro-4-oxo-3H-quinazolinyl (e.g.,2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl);1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl (e.g.,1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl);1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g.,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl);1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g.,1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl);2-oxobenz[c,d]indolyl; 1,1-dioxo-2H-naphth[1,8-c,d]isothiazolyl; and1,8-naphthylenedicarboxamido. Heterocyclic groups also include groups ofthe formula

where

F′ is selected from the group consisting of —CH₂—, —CH₂O— and —O—, andG′ is selected from the group consisting of —C(O)— and—(C(R′)(R″))_(v)—, where each of R′ and R″ is, independently, selectedfrom the group consisting of hydrogen or alkyl of one to four carbonatoms, and v is one to three and includes groups, such as1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like. Any of theheterocyclyl groups mentioned herein may be optionally substituted withone, two, three, four or five substituents independently selected fromthe group consisting of: (1) alkanoyl (e.g., formyl, acetyl, and thelike); (2) alkyl (e.g., alkoxyalkylene, alkylsulfinylalkylene,aminoalkylene, azidoalkylene, acylalkylene, haloalkylene (e.g.,perfluoroalkyl), hydroxyalkylene, nitroalkylene, or thioalkoxyalkylene);(3) alkenyl; (4) alkynyl; (5) alkoxy (e.g., perfluoroalkoxy); (6)alkylsulfinyl; (7) aryl; (8) amino; (9) aryl-alkylene; (10) azido; (11)cycloalkyl; (12) cycloalkyl-alkylene; (13) cycloalkenyl; (14)cycloalkenyl-alkylene; (15) halo; (16) heterocyclyl (e.g., heteroaryl);(17) (heterocyclyl)oxy; (18) (heterocyclyl)aza; (19) hydroxy; (20) oxo;(21) nitro; (22) sulfide; (23) thioalkoxy; (24) —(CH₂)_(q)CO₂R^(A),where q is an integer from zero to four, and R^(A) is selected from thegroup consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d)aryl-alkylene; (25) —(CH₂)_(q)CONR^(B)R^(C), where q is an integer fromzero to four and where R^(B) and R^(C) are independently selected fromthe group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d)aryl-alkylene; (26) —(CH₂)_(q)SO₂R^(D), where q is an integer from zeroto four and where R^(D) is selected from the group consisting of (a)alkyl, (b) aryl, and (c) aryl-alkylene; (27) —(CH₂)_(q)SO₂NR^(E)R^(F),where q is an integer from zero to four and where each of R^(E) andR^(F) is, independently, selected from the group consisting of (a)hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene; (28) thiol; (29)aryloxy; (30) cycloalkoxy; (31) arylalkoxy; (31) heterocyclyl-alkylene(e.g., heteroaryl-alkylene); (32) silyl; (33) cyano; and (34) —S(O)R^(H)where R^(H) is selected from the group consisting of (a) hydrogen, (b)alkyl, (c) aryl, and (d) aryl-alkylene. In some embodiments, each ofthese groups can be further substituted as described herein. Forexample, the alkylene group of an aryl-C₁-alkylene or aheterocyclyl-C₁-alkylene can be further substituted with an oxo group toafford the respective aryloyl and (heterocyclyl)oyl substituent group.In addition, when a heterocyclyl group is present in a bioreversiblegroup of the invention it may be substituted with an ester, thioester,or disulfide group that is bound to a conjugating moiety, a hydrophilicfunctional group, or an auxiliary moiety as defined herein.

By “heterocyclic radical alkyl,” as used herein, represents an alkylgroup substituted with a heterocyclic radical. The heterocyclic radicaland alkyl portions may be substituted as the individual groups asdescribed herein.

By “hydroxyalkyl” is meant —R′(R″)_(n), where n 1 or 2, R′ is alkyleneand R″ is hydroxyl, as defined herein. R′ can be further optionallysubstituted in the same manner as alkyl.

By “hydroxyaryl” is meant —R′(R″)_(n), where n is 1 or 2, R′ is aryleneand R″ is hydroxyl, as defined herein. R′ can be further optionallysubstituted in the same manner as aryl.

By “hydroxyl” is meant —OH.

By “hydroxyl protecting group” is meant any group capable of protectingthe oxygen atom to which it is attached from reacting or bonding.Hydroxyl protecting groups are known in the art, e.g., as described inWuts, Greene's Protective Groups in Organic Synthesis,Wiley-Interscience, 4th Edition, 2006. Exemplary protecting groups (withthe oxygen atom to which they are attached) are independently selectedfrom the group consisting of esters, carbonates, carbamates, sulfonates,and ethers. In exemplary ester hydroxyl protecting groups, R of the acylgroup is C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl),carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl),monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specificexamples of acyl groups for use in esters include formyl, benzoylformyl,acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl,methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl),3-phenylpropionyl, 4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl,pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl(e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted orsubstituted, e.g., p-methoxybenzoyl, phthaloyl (including salts, such atriethylamine and potassium), p-bromobenzoyl, and2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl group presentin an ester group has from 1 to 4 heteroatoms selected independentlyfrom O, N, and S. In exemplary carbonate hydroxyl protecting groups, Ris C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl),C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl),carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl),monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specificexamples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, t-butyl,p-nitrobenzyl, and benzyl carbonates. As defined herein, any heteroarylgroup present in a carbonate group has from 1 to 4 heteroatoms selectedindependently from O, N, and S. In exemplary carbamate hydroxylprotecting groups, each R is independently H, C₁₋₁₂ alkyl (e.g., C₁₋₈,C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈,C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g.,C₆₋₁₅, C₆₋₁₀, C₀₈₋₂₀, and C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g.,C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl),(C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or(C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specific examples include N-phenyl andN-methyl-N-(o-nitrophenyl) carbamates.

As defined herein, any heteroaryl group present in a carbamate group hasfrom 1 to 4 heteroatoms selected independently from O, N, and S.Exemplary ether hydroxyl protecting groups include C₁₋₁₂ alkyl (e.g.,C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g.,C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, (C₁₋₆)heteroaryl(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylthio(C₁₋₆)alkyl,(C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, and silyl (e.g., tri(C₁₋₆alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)silyl, di(C₆₋₁₀ aryl orC₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl, and (C₆₋₁₀ aryl or C₁₋₆heteroaryl)di(C₁₋₆ alkyl)silyl). Specific examples of alkylethersinclude methyl and t-butyl, and an example of an alkenyl ether is allyl.Ether hydroxyl protecting groups can be used to protect a carboxyl group(e.g., with a C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆alkyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl,(C₁₋₆)alkylthio(C₁₋₆)alkyl, or (C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl).Examples of alkoxyalkyls and alkylthioalkyls that can be used as etherhydroxyl protecting groups include methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, and β-(trimethylsilyl)ethoxymethyl. Examples ofarylalkyl groups that can be used as ether hydroxyl protecting groupsinclude benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl,triphenylmethyl (trityl), o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolylethers. Specific examples of silylethers include trimethylsilyl (TMS),triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl(TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. Anexample of an arylalkyloxyalkylether is benzyloxymethyl ether. Asdefined herein, any heteroaryl group present in an ether group has from1 to 4 heteroatoms selected independently from O, N, and S. Vicinal or1,3-diols may be protected with a diol protecting group (e.g., toproduce a “cyclic protected diol”), such as acetal (e.g., containingC₁₋₆ alkylene), ketal (e.g., containing C₃₋₆ alkylene or C₃₋₆cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate.Examples of acetal and ketal groups include methylene-dioxo,ethylidene-dioxo, benzylidene-dioxo, isopropylidene-dioxo,cyclohexylidene-dioxo, and cyclopentylidene-dioxo. An example of acyclic silylene is di-t-butylsilylene. Another diol protecting group is1,1,3,3-tetraisopropylsiloxanediyl. Examples of cyclic boronates includemethyl, ethyl, phenyl, and 2,6-diacetamidophenyl boronates. Protectinggroups may be substituted as is known in the art; for example, aryl andarylalkyl groups, such as phenyl, benzyl, naphthyl, or pyridinyl, can besubstituted with C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro, cyano, carboxyl, orhalogen. Alkyl groups, such as methyl, ethyl, isopropyl, n-propyl,t-butyl, n-butyl, and sec-butyl, and alkenyl groups, such as vinyl andallyl, can also be substituted with oxo, arylsulfonyl, halogen, andtrialkylsilyl groups. Preferred protecting groups are TBS and Piv.Protecting groups that are orthogonal are removed under differentconditions, as in known in the art.

By “imido” is meant —NR₂, where each R is independently optionallysubstituted acyl.

By “ketal” is meant —O—CR₂—O—, where each R is independently optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted arylalkyl, or a bond to thechain of carbon atoms within an intermediate in the synthesis of thehalichondrin macrolide; or both R groups are together optionallysubstituted alkylene.

By “macrocyclization” is meant a reaction converting a non-macrocycliccompound into a compound containing at least one n-membered ring, wheren is equal to or greater than 16.

By “MNBA” is meant 2-methyl-6-nitrobenzoic anhydride.

By “non-enolizable” is meant a group that, either alone or incombination with a group to which it is attached, cannot form an enolthrough a deprotonation/reprotonation sequence. For example, a“non-enolizable alkyl” can be bonded to a sulfone group or to a carbonylgroup through a quaternary carbon atom (i.e., the carbon atom that isnot bonded to a hydrogen atom).

By “non-macrocyclic” is meant a compound not containing rings orcontaining one or more m-membered rings, where m is less than or equalto 15.

By “N-protecting group” is meant a group protecting a nitrogen atom in amolecule from participating in one or more undesirable reactions duringchemical synthesis (e.g., oxidation reactions, or certain nucleophilicand electrophilic substitutions). Commonly used N-protecting groups aredisclosed in Wuts, Greene's Protective Groups in Organic Synthesis,Wiley-Interscience, 4th Edition, 2006. Exemplary N-protecting groupsinclude acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl,pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containinggroups (e.g., benzenesulfonyl, p-toluenesulfonyl,o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forminggroups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl),arylalkyl (e.g., triphenylmethyl); silyl groups (e.g., trimethylsilyl);and imine-forming groups (e.g., diphenylmethylene). PreferredN-protecting groups are acetyl, benzoyl, phenylsulfonyl,p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl,t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

By “oxo” or (O) is meant ═O.

By “pharmaceutically acceptable salt” is meant a salt within the scopeof sound medical judgment, suitable for use in contact with the tissuesof humans and animals without undue toxicity, irritation, allergicresponse and the like and commensurate with a reasonable benefit/riskratio. Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. Representative acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like.A preferred salt is the mesylate salt.

By “silyl” is meant —SiR₃, where each R is independently alkyl, alkenyl,aryl, or arylalkyl. Examples of silyl groups include tri(C₁₋₆alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)silyl, di(C₆₋₁₀ aryl orC₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl, and (C₆₋₁₀ aryl or C₁₋₆heteroaryl)di(C₁₋₆ alkyl)silyl. It will be understood that, when a silylgroup includes two or more alkyl, alkenyl, aryl, heteroaryl, orarylalkyl groups, these groups are independently selected. As definedherein, any heteroaryl group present in a silyl group has from 1 to 4heteroatoms selected independently from O, N, and S. Silyl can beoptionally substituted in the same manner as defined for each R group.

By “silylene” is meant —SiR₂—, where each R is independently alkyl,alkenyl, aryl, arylalkyl, or alkoxy. By “dialkylsilylene” is meant asilylene, where each R is alkyl. Silylene can be optionally substitutedin the same manner as defined for each R group. Silylene-dioxo is agroup having the formula —O—SiR₂—O—.

By “strong base” is meant a Brønsted base, the conjugate acid of whichhas pKa that is greater than or equal to 13. Non-limiting examples ofstrong bases include alkyl alkali metals (e.g., butyl lithium orSchlosser's base), Grignard reagents (e.g., alkyl magnesium halide),alkoxides (e.g., tertiary alkoxides, such as t-butoxide), amides (e.g.,diisopropylamide, tetramethylpiperidide, or bis(trimethylsilyl)amide),and phosphazene bases (e.g., Schwesinger base).

By “sulfonamide” is meant —NR, where R is sulfonyl.

By “sulfonate” is meant —OS(O)₂R, where R is optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl. In exemplary sulfonates, R is C₁₋₁₂alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), carbocyclicC₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g.,C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl,or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl grouppresent in a sulfonate group has from 1 to 4 heteroatoms selectedindependently from O, N, and S.

By “sulfonyl” is meant —S(O)₂R, where R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted arylalkyl, or silyl. Preferred R groups for sulfonyl are thesame as those described above for sulfonates.

By “thioacetal” is meant —S—(CHR)—S—, where R is H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “thioketal” is meant —S—(CR₂)—S—, where each R is independentlyoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “triflate” is meant trifluoromethanesulfonate.

The pKa values recited herein refer to the pKa values of a conjugateBrønsted acid in water at room temperature, unless stated otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scheme showing preparation of a halichondrin macrolideinvolving a C.2-C.3 bond-forming macrocyclization throughHorner-Wadsworth-Emmons olefination.

FIG. 2 is a scheme showing preparation of a halichondrin macrolideinvolving a C.2-C.3 bond-forming macrocyclization through ring-closingolefin metathesis.

FIG. 3 is a scheme showing preparation of a halichondrin macrolideinvolving a C.3-C.4 bond-forming macrocyclization through ring-closingolefin metathesis.

FIG. 4 is a scheme showing preparation of a halichondrin macrolideinvolving a C.12-C.13 bond-forming macrocyclization through ring-closingolefin metathesis.

FIG. 5 is a scheme showing preparation of a halichondrin macrolideinvolving a C.15-C.16 bond-forming macrocyclization through ring-closingolefin metathesis.

FIG. 6 is a scheme showing preparation of a halichondrin macrolideinvolving a C.19-C.20 bond-forming macrocyclization throughNozaki-Hiyama-Kishi reaction.

FIG. 7 is a scheme showing preparation of a halichondrin macrolideinvolving a C.26-C.27 bond-forming macrocyclization throughNozaki-Hiyama-Kishi reaction.

DETAILED DESCRIPTION

The present invention provides methods for the synthesis of ahalichondrin macrolide (see Chart 1) through a macrocyclization.Preferably, the halichondrin macrolide is a halichondrin B macrolide.The macrocyclizations of the present invention involve subjecting anon-macrocyclic intermediate to a carbon-carbon bond-forming reaction(e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmonsolefination), catalytic Ring-Closing Olefin Metathesis, orNozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate(e.g., a compound of formula (IB), (IIIB), (IVB), (VB), (VIB), or(VIIB)). The carbon-carbon bond forming reaction provides C.2-C.3,C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27 bond in thestructure of a halichondrin macrolide. The carbon-atom numbering schemefor a halichondrin macrolide is shown in Chart 1.

in which

-   -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -   where each P′ is independently H or a hydroxyl protecting            group;

    -   each of A₁ and A₂ is independently H or OP″, where each P″ is        independently H or a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2.

In some embodiments of the halichondrin macrolide, C and D′ are not thesame, and a designates (S)-stereogenic center. In certain embodiments ofthe halichondrin macrolide, one of D and D′ is optionally substitutedalkyl or OP₁, the other of D and D′ is H, and G is O. In particularembodiments of the halichondrin macrolide, one and only one of D and D′is OP₁, where P₁ is H, alkyl, or a hydroxyl protecting group. In oneembodiment of the halichondrin macrolide, k is 1, E is optionallysubstituted alkyl (e.g., Me); and D is a group of formula (1); infurther embodiments, L is —(CH(OP₂))—, R₁ and P₁ combine to form a bond,R₂ is —(CH₂)_(n)OP₃, each of P₂ and P₃ is H, and n is 1 or 2 (e.g., n is2).

The invention also provides intermediates in the synthesis ofhalichondrin and analogs of the macrolide in the structure ofhalichondrin and methods of preparing the same, as described herein.

C.2-C.3 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Horner-Wadsworth-Emmons olefination) thatprovides a C.2-C.3 bond in a halichondrin macrolide. The generalsynthetic sequence including Horner-Wadsworth-Emmons olefination thatcan be used to prepare a halichondrin macrolide is shown in FIG. 1. Asshown in FIG. 1, the non-macrocyclic intermediate in the synthesis ofthe halichondrin macrolide can be a compound of formula (IA):

-   -   or a salt or a tautomer thereof,    -   in which    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, where P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group.

In certain embodiments of the compound of formula (IA), R₃ is H or ahydroxyl protecting group, R₄ and R₅ combine to form a double bond, P₄is independently H or a hydroxyl protecting group, and X₁ is oxo. Inother embodiments of the compound of formula (IA), R₃ and R₄ combine toform a bond, and R₅ is H.

A macrocyclic intermediate in the synthesis of a halichondrin macrolidecan be a compound of formula (IB), which can be produced by reacting thecompound of formula (IA) with an organic base and a Lewis acid. Thecompound of formula (IB) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where all variables are as defined for compound of formula (IA).

The reaction conditions that can be used to convert the compound offormula (IA) into the compound of formula (IB) include those known inthe art for Horner-Wadsworth-Emmons reaction, e.g., Masamune-Roushconditions or Helquist protocol. In particular, the compound of formula(IA) can be reacted with an organic base (e.g., an organic base, theconjugate acid of which has a pKa of from 11±2) and a Lewis acid (e.g.,a salt of Li, Mg, or Zn). Non-limiting examples of an organic base thatcan be used in the Horner-Wadsworth-Emmons reaction includetrialkylamines (e.g., triethylamine or Hünig's base), DBU, and DBN.Non-limiting examples of Lewis acids that can be used in theHorner-Wadsworth-Emmons reaction include LiCl, Zn(OTf)₂, and MgCl₂.

The compound of formula (IB), in which, e.g., P₅ is a hydroxylprotecting group, can be converted into a halichondrin macrolide byreacting the compound of formula (IB) with a hydroxyl protecting groupremoving agent (e.g., a fluoride source, if the hydroxyl protectinggroup is a silyl group).

If, in the compound of formula (IB), each P₄ is H, and X₁ is oxo, thesynthesis may further involve a reaction with a Brønsted acid (e.g., aBrønsted acid having a pKa of 5±3) after the reaction of the compound offormula (IB) with a hydroxyl protecting group removing agent (e.g., toconvert P₄ from a hydroxyl protecting group into H).

If, in the compound of formula (IB), X₁ is oxo, R₃ is a hydroxylprotecting group, and R₄ and R₅ combine to form a double bond, treatmentwith a hydroxyl protecting group removing agent can provide the compoundof formula (IB), in which R₃ and R₄ combine to form a bond, and R₅ is H.

The compound of formula (IA) or formula (IB), in which X₁, together withthe carbon atom to which it is attached, is —(CH(OP_(Y)))—, where P_(Y)is H, may be treated with an oxidizing agent capable of oxidizinghydroxyl to a carbonyl group (e.g., Dess-Martin periodinane or adimethylsulfonium compound) to give the compound of formula (IA) orformula (IB), in which X₁ is oxo.

Preparation of certain compounds of formula (IB) may further involveconversion of the compound of formula (IB), in which A₁ is H, and R₄ andR₅ combine to form a double bond, into the compound of formula (IB) inwhich R₄ and A₁ combine to form oxo. In a non-limiting example, theenone in the compound of formula (IB), in which R₄ and R₅ combine toform a double bond can be converted into a C.12-C.13 epoxide using anucleophilic peroxide agent, e.g., t-butyl hydroperoxide, which can thenbe converted into the compound of formula (IB), in which A₁ and R₄combine to form oxo, using methods known in the art, e.g., by reactingwith a bidentate phosphine ligand and a source of Pd(0) (see, e.g.,Muzart, J., Eur. J. Org. Chem., 4717-4741, 2011). Thus, the compound offormula (IB), in which A₁ is OP″, can be prepared. Other transformationsmay involve α-oxygenation to produce the compound of formula (VIB), inwhich R₅ is OP″.

As described herein, one of skill in the art can identify the sequenceof reactions involving hydroxyl protecting group removing agents andBrønsted acids to convert the compound of formula (IB) into ahalichondrin macrolide.

C.2-C.3 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.2-C.3 bond in a halichondrin macrolide. Thegeneral synthetic sequence including RCM that can be used to prepare thehalichondrin macrolide is shown in FIG. 2. As shown in FIG. 2, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (IIA):

-   -   or a salt or a tautomer thereof,    -   in which    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, where P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group.

In certain embodiments of the compound of formula (IIA), R₃ is H or ahydroxyl protecting group, R₄ and R₅ combine to form a double bond, P₄is independently H or a hydroxyl protecting group, and X₁ is oxo. Inparticular embodiments of formula (IIA), X₁, together with the carbonatom to which it is attached, is —(CH(OP_(Y)))—, where P_(Y) is H. Insome embodiments of formula (IIA), X₁ is oxo. In other embodiments ofthe compound of formula (IIA), R₃ and R₄ combine to form a bond, and R₅is H.

A macrocyclic intermediate in the synthesis of a halichondrin macrolidecan be a compound of formula (IB), which can be produced by reacting thecompound of formula (IIA) with an olefin metathesis catalyst. Thecompound of formula (IB) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where all variables are as defined for compound of formula        (IIA).

The catalysts that can be used to convert the compound of formula (IIA)to the compound of formula (IB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts). Olefin metathesis-competent catalysts thatmay be used in this reaction are known in the art (e.g., secondgeneration Hoveyda-Grubbs-type catalysts, e.g., those in which theRu-benzylidene moiety is modified to include electron-withdrawing and/orelectron-donating groups).

The compound of formula (IIA) or formula (IB), in which X₁, togetherwith the carbon atom to which it is attached, is —(CH(OP_(Y)))—, whereP_(Y) is H, may be treated with an oxidizing agent capable of oxidizinghydroxyl to a carbonyl group (e.g., Dess-Martin periodinane or adimethylsulfonium compound) to give the compound of formula (IIA) orformula (IB), in which X₁ is oxo.

The halichondrin macrolide can be prepared from the compound of formula(IB) as described herein.

C.3-C.4 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.3-C.4 bond in a halichondrin macrolide. Thegeneral synthetic sequence including RCM that can be used to prepare thehalichondrin macrolide is shown in FIG. 3. As shown in FIG. 3, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (IIIA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is H or a hydroxyl protecting group.

In certain embodiments of the compound of formula (IIIA), R₃ is H or ahydroxyl protecting group, R₄ and R₅ combine to form a double bond, P₄is independently H or a hydroxyl protecting group, and X₁ is oxo. Inother embodiments of the compound of formula (IIIA), R₃ and R₄ combineto form a bond, and R₅ is H. In particular embodiments of formula(IIIA), X₁, together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, where P_(Y) is H. In some embodiments of formula (IIIA),X₁ is oxo.

A macrocyclic intermediate in the synthesis of a halichondrin macrolidecan be a compound of formula (IIIB), which can be produced by reactingthe compound of formula (IIIA) with an olefin metathesis catalyst. Thecompound of formula (IIIB) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where all variables are as defined for the compound of formula        (IIIA).

The catalysts that can be used to convert the compound of formula (IIA)to the compound of formula (IIIB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts). Olefin metathesis-competent catalysts thatmay be used in this reaction are known in the art (e.g., secondgeneration Hoveyda-Grubbs-type catalysts, e.g., those in which theRu-benzylidene moiety is modified to include electron-withdrawing and/orelectron-donating groups).

The halichondrin macrolide can be prepared from the compound of formula(IIIB), as described for the synthesis involving the compound of formula(IB), as the C.3-C.4 double bond can undergo isomerization to give thecompound of formula (IB) described herein upon exposure to basic (e.g.,isomerization mediated by a hydroxyl protecting group removing agent,such as a fluoride source) or acidic (e.g., isomerization mediated by aBrønsted acid) conditions.

The compound of formula (IIA) or formula (IIIB), in which X₁, togetherwith the carbon atom to which it is attached, is —(CH(OP_(Y)))—, whereP_(Y) is H, may be treated with an oxidizing agent capable of oxidizinghydroxyl to a carbonyl group to give the compound of formula (IIIA) orformula (IIIB), in which X₁ is oxo.

Preparation of the halichondrin macrolide may further involve conversionof the compound of formula (IIIB), in which A₁ is H, and R₄ and R₅combine to form a double bond, into the compound of formula (VIB) inwhich R₄ and A₁ combine to form oxo. In a non-limiting example, theenone in the compound of formula (IIIB), in which R₄ and R₅ combine toform a double bond can be converted into a C.12-C.13 epoxide using anucleophilic peroxide agent, e.g., t-butyl hydroperoxide, which can thenbe converted into the compound of formula (IIIB), in which A₁ and R₄combine to form oxo, using methods known in the art, e.g., by reactingwith a bidentate phosphine ligand and a source of Pd(0) (see, e.g.,Muzart, J., Eur. J. Org. Chem., 4717-4741, 2011). Thus, the halichondrinmacrolide, in which A₁ is OP″, can be prepared. Other transformationsmay involve α-oxygenation to produce the halichondrin macrolide, inwhich R₅ is OP″.

C.12-C.13 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.12-C.13 bond in a halichondrin macrolide. Thegeneral synthetic sequence including RCM that can be used to prepare thehalichondrin macrolide is shown in FIG. 4. As shown in FIG. 4, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (IVA):

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   (i) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;

    -   (ii) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;

    -   or

    -   (iii) R₃ and R₄ combine to form a bond, and R₅ is H;

    -   each P₄ and P₅ is independently H or a hydroxyl protecting        group; and

    -   R₆ is H, and P₆ is H or a hydroxyl protecting group; or R₆ and        P₆ combine to form a double bond.

In certain embodiments of the compound of formula (IVA), P₅ is H. Inparticular embodiments of the compound of formula (IVA), R₃ and R₄combine to form a bond, and R₅ is H. In some embodiments, R₆ is H, andP₆ is H or a hydroxyl protecting group. In other embodiments, R₆ and P₆combine to form a double bond.

A macrocyclic intermediate in the synthesis of a halichondrin macrolidecan be a compound of formula (IVB), which can be produced by reactingthe compound of formula (IVA) with an olefin metathesis catalyst. Thecompound of formula (IVB) has the following structure:

-   -   or a salt thereof,    -   where all variables are as defined for the compound of formula        (IVA).

The catalysts that can be used to convert the compound of formula (IVA)to the compound of formula (IVB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts). Olefin metathesis-competent catalysts thatmay be used in this reaction are known in the art (e.g., secondgeneration Hoveyda-Grubbs-type catalysts, e.g., those in which theRu-benzylidene moiety is modified to include electron-withdrawing and/orelectron-donating groups).

The compound of formula (IVB) (e.g., the compound of formula (IVB), inwhich R₆ and P₆ combine to form a double bond) can be converted to thehalichondrin macrolide by a reaction with a Brønsted acid (if each of P₄and P₅ is independently H or a hydroxyl protecting group capable ofbeing deprotected by the Brønsted acid). Alternatively, if at least oneP₄ or P₅ is a hydroxyl protecting group that is not capable of beingdeprotected by the Brønsted acid, the compound of formula (IVB) can bereacted with a hydroxyl protecting group removing agent to effect theremoval of at least one hydroxyl protecting group, provided that theproduct of the reaction is the compound of formula (IVC):

-   -   or a salt thereof,    -   where each of A₁ and A₂ is H or OP″, where P″ is H or a hydroxyl        protecting group;    -   and the remaining variables are as defined for the compound of        formula (IVA).

In a non-limiting example of the transformation of the compound offormula (IVB) to provide the compound of formula (IVC), at least one ofP₄ and P₅ is a silyl, and the hydroxyl protecting group removing agentis a fluoride source.

The compound of formula (IVC) can then be converted to the halichondrinmacrolide by a reaction with a Brønsted acid.

If, in the compound of formula (IVB) or (IVC), R₃ is a hydroxylprotecting group, and R₄ and R₅ combine to form a double bond, treatmentwith a hydroxyl protecting group removing agent can provide the compoundof formula (IVB) or (IVC), in which R₃ and R₄ combine to form a bond,and R₅ is H.

Preparation of the compound of formula (IVC) from the compound offormula (IVB) may further involve reaction with a hydroxyl protectinggroup removing agent to convert P₆ in the compound of formula (IVB) to Hand subsequent reaction with an oxidizing agent capable of converting ahydroxyl group into a carbonyl (e.g., capable of oxidizing allylicalcohol into an enone). In a non-limiting example, the enone in thecompound of formula (IVB) formed through the oxidation can then beconverted into a C.12-C.13 epoxide using a nucleophilic peroxide agent,e.g., t-butyl hydroperoxide, which can then be converted into thecompound of formula (IVB), in which A₁ and R₄ combine to form oxo, usingmethods known in the art, e.g., by reacting with a bidentate phosphineligand and a source of Pd(0) (see, e.g., Muzart, J., Eur. J. Org. Chem.,4717-4741, 2011). Thus, the compound of formula (IVC), in which A₁ isOP″, can be prepared. Other transformations may involve α-oxygenation toproduce the compound of formula (IVC), in which A₂ is OP″.

As described herein, one of skill in the art can identify the sequenceof reactions involving the reactions described above to convert thecompound of formula (IVB) into a halichondrin macrolide with or withoutthe isolation of the compound of formula (IVC).

C.15-C.16 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.15-C.16 bond in a halichondrin macrolide. Thegeneral synthetic sequence including RCM that can be used to prepare thehalichondrin macrolide is shown in FIG. 5. As shown in FIG. 5, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (VA):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkyl            ether, and R₅ is H;        -   (a2) R₃ is H or a hydroxyl protecting group, and R₄ and R₅            combine to form a double bond;        -   or        -   (a3) R₃ and R₄ combine to form a bond, and R₅ is H;        -   (b1) A₁ and R₇ combine to form oxo, R₆ is H or a hydroxyl            protecting group, and R₈ is H;        -   or        -   (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₆ is H or a hydroxyl protecting group, and R₇ and                R₈ combine to form a double bond;            -   or            -   (ii) R₆ and R₇ combine to form a bond, and R₈ is H or                OP″;        -   (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;        -   or        -   (c2) R₉ and P₄ combine to form a double bond;

    -   R₁₀ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₁₁)₂—, or NP₆,        and where each R₁₁ is independently H or —COOR₁₂, P₆ is an        N-protecting group, and R₁₂ is alkyl; and

    -   each P₅ is independently H or a hydroxyl protecting group.

In certain embodiments of the compound of formula (VA), R₆ and R₇combine to form a bond, and R₈ is H. In particular embodiments of thecompound of formula (VA), R₃ and R₄ combine to form a bond, and R₅ is H.In some embodiments of the compound of formula (VA), each P₅ isindependently a hydroxyl protecting group. In further embodiments of thecompound of formula (VA), R₉ is H, and P₄ is a hydroxyl protectinggroup. In other embodiments, A₁ is H.

A macrocyclic intermediate in the synthesis of a halichondrin macrolidecan be a compound of formula (VB), which can be produced by reacting thecompound of formula (VA) with an olefin metathesis catalyst. Thecompound of formula (VB) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where all variables are as defined for the compound of formula        (VA).

The catalysts that can be used to convert the compound of formula (VA)to the compound of formula (VB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts). Olefin metathesis-competent catalysts thatmay be used in this reaction are known in the art (e.g., secondgeneration Hoveyda-Grubbs-type catalysts, e.g., those in which theRu-benzylidene moiety is modified to include electron-withdrawing and/orelectron-donating groups).

The compound of formula (VB) can be reacted with a hydroxyl protectinggroup removing agent and, optionally, an oxidizing agent (e.g., when R₉is H in the compound of formula (VB)) capable of converting an alcoholto a carbonyl group (e.g., capable of converting an allylic alcohol toan enone) to afford the compound of formula (VBa):

-   -   or a salt thereof,    -   where A₂ is H or OP″, and the remaining variables are as defined        for the compound of formula (VA).

The compound of formula (VBa) can be reacted with a 1,4-reducing agentto furnish the compound of formula (VC):

-   -   or a salt thereof,    -   where all variables are as defined for the compound of formula        (VBa).

The 1,4-reducing agents include copper (I) hydrides, which can beisolated (e.g., Stryker's reagent) or prepared in situ (e.g., from acopper (I) or copper (11) salt and a hydride source). Catalyticquantities of a copper salt (either copper (I) or copper (11) salt) incombination with stoichiometric or superstoichiometric quantities of ahydride source (e.g., a borohydride salt, borane, PMHS, or a hydrosilane(e.g., Ph₂SiH₂)). A non-limiting example of the reaction conditions thatcan be used in the reaction sequence from the compound of formula (VB)to the compound of formula (VC) are described, e.g., in Baker et al.,Org. Lett., 10:289-292, 2008, the disclosure of which is incorporatedherein by reference. Other metals can be used to catalyze 1,4-reduction,e.g., Ru, Pd, and Ir compounds.

Alternatively, if R₉ and P₄ combine to form a double bond in thecompound of formula (VB), the reaction of the compound of formula (VB)with a hydroxyl protecting group removing agent can furnish the compoundof formula (VC) directly.

If the compound of formula (VC) includes hydroxyl protecting groups asP₅, these hydroxyl protecting groups can be removed with a hydroxylprotecting group removing agent to give the compound of formula (IVC):

-   -   or a salt thereof,    -   where all variables are as defined for the compound of formula        (VBa).

The halichondrin macrolide can be prepared from the compound of formula(IVC) as described herein.

C.19-C.20 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) thatprovides a C.19-C.20 bond in a halichondrin macrolide. The generalsynthesis sequence including NHK that can be used to prepare thehalichondrin macrolide is shown in FIG. 6. As shown in FIG. 6, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (VIA):

-   -   or a salt or a tautomer thereof,    -   where    -   b designates (R)-stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or b designates (S)-stereogenic        center, and Z is OR₆, where R₆ is a hydroxyl protecting group;    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   Y is iodide, bromide, or trifluoromethanesulfonate;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   and

    -   each P₄ is independently H or a hydroxyl protecting group, and        X₁ is oxo; or both P₄ groups and X₁, together with the atoms to        which each is attached, combine to form ketal.

In particular embodiments of the compound of formula (VIA), R₃ and R₄combine to form a bond, and R₅ is H. In some embodiments of the compoundof formula (VIA), both P₄ groups and X₁, together with the atoms towhich each is attached, combine to form ketal.

An intermediate in the synthesis of the halichondrin macrolide can be acompound of formula (VIB), which can be produced by subjecting thecompound of formula (VIA) to Nozaki-Hiyama-Kishi reaction conditions(e.g., by reacting with a Cr(II) salt and a Ni(II) salt). The compoundof formula (VIB) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where        -   b designates (R)-stereogenic center, c designates            (S)-stereogenic center, and Z is a sulfonate, chloride,            bromide, or iodide;        -   or        -   b designates (S)-stereogenic center, c designates            (R)-stereogenic center, and Z is OR₆, where R₆ is a hydroxyl            protecting group;    -   and the remaining variables are as defined for the compound of        formula (VIA).

Nozaki-Hiyama-Kishi reaction conditions that may be used to prepare thecompound of formula (VIB) from the compound of formula (VIA) can bethose known in the art. Nozaki-Hiyama-Kishi reaction on the compound offormula (VIA) can include reacting the compound of formula (VIA) with aCr(II) salt and a Ni(II) salt. Ancillary ligands can be used incombination with the metal salts. In a non-limiting example, asubstituted 1,10-phenanthroline can be used in combination with a Ni(II)salt. Chiral ancillary ligands can be used to render the reactionstereoselective. In a non-limiting example, chiralN-(dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(II) saltto control the stereochemistry of the carbonyl carbon, to which a vinylnucleophile is added in the course of Nozaki-Hiyama-Kishi reaction.

The compound of formula (VIB) can be converted to the halichondrinmacrolide using the step of nucleophilic ring-closing of the compound offormula (VIB).

In particular, the compound of formula (VIB) (in which Z is a sulfonate,chloride, bromide, or iodide; b designates (R)-stereogenic center; and cdesignates (S)-stereogenic center) can be converted to the halichondrinmacrolide directly, e.g., upon isolation from the Nozaki-Hiyama-Kishireaction mixture (e.g., by treatment with a base) or by contacting amixture containing the product of the Nozaki-Hiyama-Kishi reaction withsilica gel. Additionally, the compound of formula (VIB) can be reactedwith a hydroxyl protecting group removing agent (before or after thestep of nucleophilic ring-closing) if, e.g., each of P₄ is a hydroxylprotecting group, optionally, with a subsequent reaction with a Brønstedacid to form a compound, in which both P₄ groups and X₁, together withthe atoms to which each is attached, combine to form ketal.

Alternatively, if, in the compound of formula (VIB), b designates(S)-stereogenic center, c designates (R)-stereogenic center, and Z isOR₆, where R₆ is a hydroxyl protecting group, the step of nucleophilicring-closing of the compound of formula (VIB) can be effected after thehydroxyl group attached to the carbon atom designated with c isconverted into a leaving group (e.g., a sulfonate by a reaction with asulfonyl electrophile, such as a sulfonyl chloride or a sulfonylanhydride). In these embodiments, the step of nucleophilic ring-closingcan be carried out by, e.g., first, reacting the compound of formula(VIB), after the conversion of the hydroxyl into the leaving group, witha hydroxyl protecting group removing agent to convert R₆ into H and thenreacting the product with a base.

Preparation of certain compounds of formula (VIB) may further involveconversion of the compound of formula (VIB), in which A₁ is H, and R₄and R₅ combine to form a double bond, into the compound of formula (VIB)in which R₄ and A₁ combine to form oxo. In a non-limiting example, theenone in the compound of formula (VIB), in which R₄ and R₅ combine toform a double bond can be converted into a C.12-C.13 epoxide using anucleophilic peroxide agent, e.g., t-butyl hydroperoxide, which can thenbe converted into the compound of formula (VIB), in which A₁ and R₄combine to form oxo, using methods known in the art, e.g., by reactingwith a bidentate phosphine ligand and a source of Pd(0) (see, e.g.,Muzart, J., Eur. J. Org. Chem., 4717-4741, 2011). Thus, the compound offormula (VIB), in which A₁ is OP″, can be prepared. Othertransformations may involve α-oxygenation to produce the compound offormula (VIB), in which R₅ is OP″.

One of skill in the art will recognize that any unprotected hydroxylgroups can be protected with a hydroxyl protecting group, if theunprotected hydroxyl groups are not intended for reacting in the step ofnucleophilic ring-closing.

C.26-C.27 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) thatprovides a C.26-C.27 bond in a halichondrin macrolide. The generalsynthesis sequence including NHK that can be used to prepare thehalichondrin macrolide is shown in FIG. 7. As shown in FIG. 7, thenon-macrocyclic intermediate in the synthesis of the halichondrinmacrolide can be a compound of formula (VIIA):

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   Y is iodide, bromide, or trifluoromethanesulfonate; and

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—, where R₈ is H or a        hydroxyl protecting group;

    -   or

    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;

    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;

    -   or

    -   (b2) Z and R₇ combine to form a double bond, and R₆ is H or a        hydroxyl protecting group.

In particular embodiments of the compound of formula (VIIA), Z and R₇combine to form a double bond, and R₆ is a hydroxyl protecting group. Insome embodiments of the compound of formula (VIIA), each P₄ isindependently H or a hydroxyl protecting group, and X₁, together withthe carbon to which it is attached, forms a carbonyl or —(CH(OR₈))—. Incertain embodiments of the compound of formula (VIIA), R₃ is H or ahydroxyl protecting group, R₄ and R₅ combine to form a double bond.

An intermediate in the synthesis of the halichondrin macrolide can be acompound of formula (VIIB), which can be produced by subjecting thecompound of formula (VIIA) to Nozaki-Hiyama-Kishi reaction conditions(e.g., by reacting with a Cr(II) salt and a Ni(II) salt). The compoundof formula (VIIB) has the following structure:

-   -   or a salt thereof,    -   where each of P₅ and R₆ is independently H or a hydroxyl        protecting group, and the remaining variables are as defined for        the compound of formula (VIIA).

Nozaki-Hiyama-Kishi reaction conditions that may be used to prepare thecompound of formula (VIIB) from the compound of formula (VIIA) can bethose known in the art. Nozaki-Hiyama-Kishi reaction on the compound offormula (VIIA) can include reacting the compound of formula (VIIA) witha Cr(II) salt and a Ni(II) salt. Ancillary ligands can be used incombination with the metal salts. In a non-limiting example, asubstituted 1,10-phenanthroline can be used in combination with a Ni(II)salt. Chiral ancillary ligands can be used to render the reactionstereoselective. In a non-limiting example, chiralN-(dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(II) saltto control the stereochemistry of the carbonyl carbon, to which a vinylnucleophile is added in the course of Nozaki-Hiyama-Kishi reaction.

The compound of formula (VIIB) can be converted to a compound of formula(VIIC) through the step of nucleophilic ring-closing of the compound offormula (VIIB), where the compound of formula (VIIC) has the followingstructure:

-   -   or a salt or a tautomer thereof,    -   where each P₄ is H or a hydroxyl protecting group, and X₁ is        oxo; or both P₄ groups and X₁, together with the atoms to which        each is attached, combine to form a ketal;    -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl protecting        group, and R₅ is H;        -   or    -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting group,        and:        -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅            combine to form a double bond;        -   or        -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″;    -   and the remaining variables are as defined for the compound of        formula (VIIA).

The step of nucleophilic ring-closing of the compound of formula (VIIB)can be effected after the hydroxyl group produced by the NHK reaction isconverted into a leaving group (e.g., a sulfonate by a reaction with asulfonyl electrophile, such as a sulfonyl chloride or a sulfonylanhydride). In these embodiments, the step of nucleophilic ring-closingcan be carried out by reacting the compound of formula (VIB), in whichR₆ is H, after the conversion of the hydroxyl into the leaving group,with a strong base (e.g., alkoxide).

Preparation of the compound of formula (VIIC) can involve Vasellafragmentation prior to the step of nucleophilic ring-closing, if Z andR₇ combine to form a double bond, and R₆ is a hydroxyl protecting groupin the compound of formula (VIIB).

The compound of formula (VIIC) can be reacted with a hydroxyl protectinggroup removing agent to give a compound of formula (VIID):

-   -   or a salt thereof,    -   where each of A₁ and A₂ is independently H or OP″, and the        remaining variables are as defined for the compound of formula        (VIIC).

The compound of formula (VIID) can be converted to the halichondrinmacrolide by reacting with a Brønsted acid (e.g., a pyridinium salt,such as pyridinium p-toluene sulfonate).

In some embodiments, the preparation of the halichondrin macrolide fromthe compound of formula (VIIA) can further involve an oxidation reaction(e.g., contacting the compound of formula (VIIA), (VIIB), or (VIIC), inwhich X₁ is —(CH(OR₈))— and R₈ is H, with an oxidizing agent capable ofoxidizing an alcohol to a carbonyl group).

Preparation of the compound of formula (VIID) from the compound offormula (VIIB) may further involve conversion of the compound of formula(VIIB), in which R₄ and R₅ combine to form a double bond into thecompound of formula (VIIC) in which R₄ and A₁ combine to form oxo. In anon-limiting example, the enone in the compound of formula (VIIB), inwhich R₄ and R₅ combine to form a double bond can be converted into aC.12-C.13 epoxide using a nucleophilic peroxide agent, e.g., t-butylhydroperoxide, which can then be converted into the compound of formula(VIIC), in which A₁ and R₄ combine to form oxo, using methods known inthe art, e.g., by reacting with a bidentate phosphine ligand and asource of Pd(0) (see, e.g., Muzart, J., Eur. J. Org. Chem., 4717-4741,2011). Thus, the compound of formula (VIID), in which A₁ is OP″, can beprepared. Other transformations may involve α-oxygenation to produce thecompound of formula (VIID), in which A₂ is OP″.

One of skill in the art will recognize that any unprotected hydroxylgroups can be protected with a hydroxyl protecting group, if theunprotected hydroxyl groups are not intended for reacting in the step ofnucleophilic ring-closing.

Synthesis of Non-Macrocyclic Intermediates

The compounds of formula (IA), (IIA), (IIIA), (IVA), (VA), (VIA), and(VIIA) can be prepared using methods and intermediates disclosed, e.g.,in U.S. Pat. Nos. 5,338,865 and 5,436,238; in International Patentapplication No. PCT/US2014/063960; and in Towle et al., Annual Meetingof the American Association for Cancer Research, Apr. 6-10, 2002, 5721;Wang et al., Bioorg. Med. Chem. Lett., 10:1029-1032, 2000; Aicher etal., J. Am. Chem. Soc., 114:3162-3164, 1992; Ueda et al., J. Am. Chem.Soc., 136:5171-5176; and Yamamoto et al., J. Am. Chem. Soc.,134:893-896, 2012; each of which is incorporated herein by reference inits entirety.

Compound (IA)

The compound of formula (IA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (IA) can be prepared from compound (IC), in whichP_(X) is H, and compound (ID), e.g., using esterification reactionconditions (e.g., Shiina esterification reaction conditions (e.g., usingMNBA) or Yamaguchi esterification reaction conditions, e.g., thereaction conditions described in Aicher et al., J. Am. Chem. Soc.,114:3162-3164, 1992).

The compound of formula (IC) has the following structure

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently optionally substituted alkyl or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   P_(X) is H or a hydroxyl protecting group;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   R₆ is OP″ and R₇ is H, or R₆ and R₇ combine to form a double        bond;

    -   each P₄ is independently a hydroxyl protecting group, and X₁ is        oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is a hydroxyl protecting group; and

    -   where each P″ is independently H or a hydroxyl protecting group.

The compound of formula (IC), in which X₁ is oxo, can be prepared byreacting an oxidizing agent capable of oxidizing hydroxyl to a carbonylgroup (e.g., Dess-Martin periodinane) with the compound of formula (IC),in which X₁, together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, where P_(Y) is H.

The compound of formula (ID) has the following structure:(RO)₂P(O)CH₂COOH, where each R is independently optionally substitutedalkyl or optionally substituted aryl.

The preparation of the compound of formula (IA) from the compound offormula (IC) and the compound of formula (ID) may involve ahydroboration/oxidation reaction to furnish the aldehyde group in thecompound of formula (IA) after the esterification reaction, if R₆ and R₇combine to form a double bond in the compound of formula (IC).Alternatively, the preparation of the compound of formula (IA) from thecompound of formula (IC) and the compound of formula (ID) may involvereacting the esterification product with a hydroxyl protecting groupremoving agent and then reacting the product with an oxidizing agentcapable of converting a hydroxyl group into a carbonyl to furnish thealdehyde group in the compound of formula (IA), if, in the compound offormula (IC) R₆ is OP and R₇ is H.

The compound of formula (IC) can be prepared from a compound of formula(IE) and the compound of formula (IF), e.g., using Nozaki-Hiyama-Kishireaction conditions, as described herein. The hydroxyl group used in thesubsequent esterification reaction can be deprotected using a hydroxylprotecting group removing agent. Specifically, the preparation of thecompound of formula (IC), in which P_(X) is H, may further involvetreating the compound of formula (IC), in which P_(X) is a hydroxylprotecting group, with a hydroxyl protecting group removing agent.

The compound of formula (IE) has the following structure:

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently optionally substituted alkyl or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   each P′ is independently a hydroxyl protecting group;    -   E is optionally substituted alkyl or optionally substituted        alkoxy;    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;    -   P_(X) is a hydroxyl protecting group;    -   k is 0 or 1;    -   n is 0, 1, or 2; and    -   X₁ is oxo.

The compound of formula (IF) has the following structure:

-   -   where    -   each R₃, P₄, and P₅ is independently a hydroxyl protecting        group;    -   A₁ is H or OP″, where P″ is a hydroxyl protecting group;    -   R₆ is OP₅, and R₇ is H, or R₆ and R₇ combine to form a double        bond;    -   and    -   Y is chloro, bromo, iodo, trifluoromethanesulfonate, or        trialkylsilane.

The compound of formula (IE), in which X₁ is oxo, can be reacted withthe compound of formula (IF) under the Nozaki-Hiyama-Kishi reactionconditions, as described herein.

The compound of formula (IE) can be accessed, e.g., from the compound offormula (VIIID).

The compound of formula (IF) can be prepared using methods known in theart, e.g., those described in WO 2015/066729.

The preparation of compound (IA) may further involve reactionsdeprotecting protected hydroxyl groups or protecting unprotectedhydroxyl groups using methods described herein.

Compound (IIA)

The compound of formula (IIA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (IIIA) can be prepared from acrylic acid a compoundof formula (IIB), e.g., using esterification reaction conditions (e.g.,Shiina esterification reaction conditions (e.g., using MNBA) orYamaguchi esterification reaction conditions, e.g., the reactionconditions described in Aicher et al., J. Am. Chem. Soc., 114:3162-3164,1992).

The compound of formula (IIB) has the following structure:

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently optionally substituted alkyl or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   P_(X) is H or a hydroxyl protecting group;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;        -   A₁ and R₄ combine to form oxo, R₃ is H or a hydroxyl            protecting group, and R₅ is H;        -   or        -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting            group, and:            -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and                R₅ combine to form a double bond;            -   or            -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H or                OP″;

    -   each P₄ is independently a hydroxyl protecting group, and X₁ is        oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal; and

    -   P₅ is a hydroxyl protecting group.

The compound of formula (IIB), in which X₁ is oxo, can be prepared byreacting an oxidizing agent capable of oxidizing hydroxyl to a carbonylgroup (e.g., Dess-Martin periodinane or a dimethylsulfonium compound)with the compound of formula (IIB), in which X₁, together with thecarbon atom to which it is attached, is —(CH(OP_(Y)))—, where P_(Y) isH.

The compound of formula (IIB), in which P_(X) is H, can be prepared byreacting a hydroxyl protecting group removing agent with the compound offormula (IIB), in which P_(X) is a hydroxyl protecting group.

In non-limiting examples, the compound of formula (IIB) can be preparedfrom a compound of formula (IE) and a compound of formula (IIC) (e.g.,via the compound of formula (IICa).

The preparation of the compound of formula (IIB) may further involvehydroboration/oxidation reaction with subsequent olefination (e.g.,Wittig reaction (e.g., with Ph₃PCH₂) to provide a terminal alkene). Forexample, compound of formula (IIC) may be subjected tohydroboration/oxidation sequence to produce an aldehyde, which upontreatment with Ph₃PCH₂, produces the compound of formula (IICa).

The compound of formula (IIC) has the following structure:

-   -   where    -   A₁ is H or OP″, where P″ is H or a hydroxyl protecting group;    -   each R₃, P₄, and P₅ is independently a hydroxyl protecting        group; and    -   Y is chloro, bromo, iodo, or trifluoromethanesulfonate.

The compound of formula (IICa) has the following structure:

where all variables are as defined for formula (IIC).

The compound of formula (IE), in which X₁ is oxo, can be reacted withthe compound of formula (IIC) under the Nozaki-Hiyama-Kishi reactionconditions, as described herein.

The compound of formula (IIC) can be prepared using methods known in theart, e.g., those described in WO 2015/066729.

The preparation of compound (IIA) may also involve reactionsdeprotecting protected hydroxyl groups or protecting unprotectedhydroxyl groups using methods described herein.

Compound (IIIA)

The compound of formula (IIA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (IIIA) can be prepared from but-3-enoic acid acompound of formula (IC), in which R₆ and R₇ combine to form a doublebond, e.g., using esterification reaction conditions (e.g., Shiinaesterification reaction conditions (e.g., using MNBA) or Yamaguchiesterification reaction conditions, e.g., the reaction conditionsdescribed in Aicher et al., J. Am. Chem. Soc., 114:3162-3164, 1992). Thepreparation of compound (IIIA) may also involve reactions deprotectingprotected hydroxyl groups or protecting unprotected hydroxyl groupsusing methods described herein.

Compound (IVA)

The compound of formula (IVA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (IVA) can be prepared from a compound of formula(IVD) and a compound of formula (IVE), e.g., using esterificationreaction conditions (e.g., Shiina esterification reaction conditions(e.g., using MNBA) or Yamaguchi esterification reaction conditions,e.g., the reaction conditions described in Aicher et al., J. Am. Chem.Soc., 114:3162-3164, 1992).

The compound of formula (IVD) has the following structure:

-   -   where    -   (i) R₃ is a hydroxyl protecting group, R₄ is alkyl ether, and R₅        is H;    -   (ii) R₃ is a hydroxyl protecting group, and R₄ and R₅ combine to        form a double bond;    -   or    -   (iii) R₃ and R₄ combine to form a bond, and R₅ is H;    -   each P₄ and P₅ is independently a hydroxyl protecting group.

The compound of formula (IVE) has the following structure:

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁; A is a group of formula (1) or a C₁₋₆ saturated        or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being        unsubstituted or having from 1 to 10 substituents independently        selected from the group consisting of cyano, halo, azido, oxo,        and Q₁, the group of formula (1) having the structure:

-   -   -   where        -   L is —(CH(OP₂))— or —C(O)—;        -   R₁ and P₁ combine to form a bond; or R₁ is H, and P₁ is            alkyl;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently optionally substituted alkyl or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2; and

    -   R₆ is H, and P₆ is H or a hydroxyl protecting group; or R₆ and        P₆ combine to form a double bond.

The compound (IVE) can be prepared using methods known in the art orusing the allene-Prins method described herein. In particular, after theallene-Prins reaction and allylic reduction, the substrate, in which R₃is

can be subjected to a reaction sequence involving reactions withoxidizing agents capable of oxidizing an alcohol to a carbonyl and vinyladdition to carbonyl.

The preparation of compound (IVA) may also involve reactionsdeprotecting protected hydroxyl groups or protecting unprotectedhydroxyl groups using methods described herein.

Compound (VA)

The compound of formula (VA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (VA) can be prepared from a compound of formula (VE)and a compound of formula (VD), in which P_(X) is H, e.g., usingesterification reaction conditions (e.g., Shiina esterification reactionconditions (e.g., using MNBA) or Yamaguchi esterification reactionconditions, e.g., the reaction conditions described in Aicher et al., J.Am. Chem. Soc., 114:3162-3164, 1992).

The compound of formula (VE) has the following structure:

-   -   where    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkyl ether,        and R₅ is H;    -   (a2) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;    -   or    -   (a3) R₃ and R₄ combine to form a bond, and R₅ is H;    -   (b1) R₆ is a hydroxyl protecting group, and R₇ and R₈ combine to        form a double bond;    -   or    -   (b2) R₆ and R₇ combine to form a bond, and R₈ is H;    -   (c1) R₉ is H, and P₄ is a hydroxyl protecting group;    -   or    -   (c2) R₉ and P₄ combine to form a double bond;    -   each P₅ is independently a hydroxyl protecting group; and    -   A₁ is H or OP″, where P″ is a hydroxyl protecting group.

The compound of formula (VD) has the following structure:

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁; A is a group of formula (1) or a C₁₋₆ saturated        or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being        unsubstituted or having from 1 to 10 substituents independently        selected from the group consisting of cyano, halo, azido, oxo,        and Q₁, the group of formula (1) having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ and P₁ combine to form a bond; or R₁ is H, and P₁ is a            hydroxyl protecting group or alkyl;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently optionally substituted alkyl or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl; P_(X) is H        or a hydroxyl protecting group;

    -   k is 0 or 1;

    -   n is 0, 1, or 2; and

    -   R₁₀ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₁₁)₂—, or NP₆,        and where each R₁₁ is independently H or —COOR₁₂, P₆ is an        N-protecting group, and R₁₂ is alkyl.

The compound of formula (VD), in which P_(X) is H, can be prepared byreacting a hydroxyl protecting group removing agent with the compound offormula (VD), in which P_(X) is a hydroxyl protecting group.

The compound of formula (VD) can be prepared using methods known in theart or using the allene-Prins method described herein. For example, thecompound of formula (VD), in which R₁₀ is —CH₂X₁CH₂CH═CH₂, can beprepared from the compound of formula (VF):

where R_(G) is —CHO, —CH═CH—COOR_(H), where R_(H) is H or a hydroxylprotecting group, and all remaining variables are as defined for formula(VD).

Thus, in a non-limiting example, the compound of formula (VF), in whichR_(G) is —CHO, may be subjected to Horner-Wadsworth-Emmons reactionconditions (e.g., with (EtO)₂P(O)—CH₂—COOR_(H)) to produce the compoundof formula (VF), in which R_(G) is —CH═CH—COOR_(H). The latter compoundmay be treated with a 1,2-reducing agent (e.g., DIBAL) followed by aquench with allyl halide (e.g., allyl bromide) to give the compound offormula (VD).

The compound of formula (VF) may be prepared from the compound offormula (VIIID). In a non-limiting example, the compound of formula(VIIID), in which R₃ is —CH₂—OP₅, and P₅ is a hydroxyl protecting group,may be treated with a hydroxyl protecting group removing agent (e.g., ifP₅ is Piv, the hydroxyl protecting group removing agent may be DIBAL),followed by an oxidizing agent capable of oxidizing hydroxyl to acarbonyl group (e.g., Dess-Martin periodinane), to give the compound offormula (VF), in which R_(G) is —CHO.

The preparation of compound (VA) may also involve reactions deprotectingprotected hydroxyl groups or protecting unprotected hydroxyl groupsusing methods described herein.

Compound (VIA)

The compound of formula (VIA) can be prepared using methods described inthe references incorporated by reference above. In particular, thecompound of formula (VIA) can be prepared from a compound of formula(VIC) and a compound of formula (VID), e.g., using esterificationreaction conditions (e.g., Shiina esterification reaction conditions(e.g., using MNBA) or Yamaguchi esterification reaction conditions,e.g., the reaction conditions described in Aicher et al., J. Am. Chem.Soc., 114:3162-3164, 1992).

The compound of formula (VIC) has the following structure:

-   -   or a tautomer thereof    -   where    -   b designates (R)-stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or b designates (S)-stereogenic        center, and Z is OR₆, where R₆ is a hydroxyl protecting group;    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅        combine to form a double bond;        -   or    -   (ii) R₃ and R₄ combine to form a bond, and R₅ is H;    -   each P₄ is independently a hydroxyl protecting group, and X₁ is        oxo or X₁, together with the carbon atom to which it is        attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl        protecting group; or both P₄ groups and X₁, together with the        atoms to which each is attached, combine to form ketal.

The compound of formula (VID) has the following structure:

-   -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ and P₁ combine to form a bond; or R₁ is absent or H, and            P₁ is absent, a hydroxyl protecting group, or alkyl;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently a hydroxyl protecting group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2; and

    -   P₅ is a hydroxyl protecting group

The compound of formula (VIC) can be prepared using methods described inWO 2015/066729.

The preparation of compound (VIA) may also involve reactionsdeprotecting protected hydroxyl groups or protecting unprotectedhydroxyl groups using methods described herein.

Compound (VIIA)

The compound of formula (VIIA) can be prepared using methods describedin the references incorporated by reference above. In particular, thecompound of formula (VIIA) can be prepared from a compound of formula(VIIE):

-   -   or a salt or a tautomer thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   Y is iodide, bromide, or trifluoromethanesulfonate;

    -   P₅ is H or a hydroxyl protecting group; and

    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—, where R₈ is H or a        hydroxyl protecting group;

    -   or

    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;

    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;

    -   or

    -   (b2) Z and R₇ combine to form a double bond, and R₆ is H or a        hydroxyl protecting group.

The preparation of the compound of formula (VIIA) can involve oxidizingthe compound of formula (VIIE) (e.g., the compound of formula (VIIE), inwhich P₅ is H or a hydroxyl protecting group), e.g., by reacting with anoxidizing agent capable of oxidizing hydroxyl to a carbonyl group. Themixture containing the oxidizing agent can also act as a hydroxylprotecting group removing agent.

The compound of formula (VIIE) can be formed by reacting a compound offormula (VIIF) with the compound of formula (VIIG). The compound offormula (VIIF) has the following structure:

-   -   or a salt or a tautomer thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate; and    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₄ is independently H or a hydroxyl        protecting group, and X₁, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₈))—, where R₈ is H or a        hydroxyl protecting group;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₄ is independently H or a hydroxyl protecting group,            and X₁, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₈))—;        -   or        -   both P₄ groups and X₁, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine to        form a bond;    -   or    -   (b2) Z and R₇ combine to form a double bond, and R₆ is H or a        hydroxyl protecting group.

The compound of formula (VIIG) has the following structure:

-   -   or a salt thereof,    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2; and

    -   P₅ is H or a hydroxyl protecting group.

Allene-Prins Reaction in the Preparation of Fragments (e.g., C.14-C.38Fragment) of Halichondrin

The invention further features a method of preparing a fragment ofhalichondrin macrolide (e.g., C.20-C.35, C.20-C.38, C.16-C.35,C.16-C.38, C.14-C35, and C.14-C.38 fragments), which can be anintermediate in the synthesis of halichondrin macrolide or a saltthereof. The advantages of the process relative to the current synthesisof C.14-C.35, C.14-C.38, C.16-C.35, C.16-C.38, C.20-C.35, and C.20-C.38fragments of halichondrin include non-metal mediated assembly that doesnot employ a C.23 leaving group. Additionally, the process obviates theneed for a chiral ligand. The method involves performing an allene-Prinsreaction on a compound of formula (VIIIA), a compound of formula(VIIIB), and R₄OH to afford the intermediate in the synthesis ofhalichondrin macrolide,

-   -   where R₄ is an optionally substituted acyl;    -   where the compound of formula (VII A) has the following        structure:

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   X is O, or X, together with the carbon atom to which it is        attached, forms —(C(OP_(z))₂)—, wherein each P_(z) is        independently optionally substituted alkyl or optionally        substituted aryl, or both P_(z) combine to form optionally        substituted alkylene or optionally substituted arylene; and

    -   P₄ is H or a hydroxyl protecting group;

    -   where the compound of formula (VIIIB) has the following        structure:

-   -   -   where P₅ is H or a hydroxyl protecting group; each P₆ is            independently a hydroxyl protecting group, or both P₆            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; and R₅ is H or            —CH₂X₁CH₂CH═CH₂, where X₁ is O, —CH₂—, or NP₇, where P₇ is a            sulfonyl;

    -   and where the intermediate is a compound of formula (VIIIC):

-   -   or a salt thereof,    -   where a designates (R)-stereogenic center or (S)-stereogenic        center.

In some embodiments, a designates (S)-stereogenic center. In certainembodiments, one and only one of D and D′ is optionally substitutedalkyl or OP₁. In other embodiments, one and only one of D and D′ is OP₁,where P₁ is H, alkyl, or a hydroxyl protecting group. In yet otherembodiments, A is a group of formula (1). In still other embodiments, Lis —(CH(OP₂))—. In particular embodiments, R₁ and P₁ combine to form abond. In certain embodiments, G is O. In further embodiments, E isoptionally substituted alkyl (e.g., methyl). In some embodiments, kis 1. In particular embodiments, R₂ is —(CH₂)_(n)OP₃ (e.g., n is 1 or2). In further embodiments, at least one of P₂ and P₃ is a hydroxylprotecting group.

The reaction conditions that can be used to prepare the compound offormula (VIIIC) using allene-Prins reaction are those known in the artfor Prins reaction and can include reacting the compound of formula(VIIIA), the compound of formula (VIIIB), and R₄OH with a Lewis acid(e.g., boron trifluoride or a solvate thereof).

The compound of formula (VIIIC) can be subjected to allylic reducingconditions to afford a compound of formula (VIIID):

-   -   or a salt thereof,    -   where    -   each of D and D′ is independently H, optionally substituted        alkyl, or OP₁, provided that only one of D and D′ is OP₁, where        P₁ is H, alkyl, or a hydroxyl protecting group; A is a group of        formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbon        skeleton, the skeleton being unsubstituted or having from 1 to        10 substituents independently selected from the group consisting        of cyano, halo, azido, oxo, and Q₁, the group of formula (1)        having the structure:

-   -   -   where        -   L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—;        -   R₁ is H, or R₁ and P₁ combine to form a bond;        -   R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ and P₃ is            independently H, optionally substituted alkyl, or a hydroxyl            protecting group, or P₂ and P₃, together with the atoms to            which each is attached, combine to form a ketal, a cyclic            carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or R₂ and            P₂ combine to form an optionally substituted ethylene or a            structure selected from the group consisting of:

-   -   -    where each P′ is independently H or a hydroxyl protecting            group;

    -   E is optionally substituted alkyl or optionally substituted        alkoxy;

    -   G is O, S, CH₂, or NR_(N), where R_(N) is H, an N-protecting        group, or optionally substituted alkyl;

    -   each Q₁ is independently OR_(A), SR_(A), SO₂R_(A), OSO₂R_(A),        NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),        NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),        (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), where each of R_(A) and        R_(B) is independently H, alkyl, haloalkyl, hydroxyalkyl,        aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl,        alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,        heterocyclic radical, or heterocyclic radical-alkyl;

    -   k is 0 or 1;

    -   n is 0, 1, or 2;

    -   and

    -   P₄ is H or a hydroxyl protecting group; and

    -   R₃ is —CH₂—OP₅, —CH═CH₂,

-   -   -   where P₅ is H or a hydroxyl protecting group; each P₆ is            independently a hydroxyl protecting group, or both P₆            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; and R₅ is H or            —CH₂X₁CH₂CH═CH₂, where X₁ is O, —CH₂—, or NP₇, where P₇ is a            sulfonyl.

Preparation of a compound of formula (VIIIB) is described in detail inInternational Patent Application No. PCT/US2014/063960, and thedisclosure of the preparation is incorporated herein by reference in itsentirety.

Compounds

The present invention also provides compounds that can be used in thesynthesis of a halichondrin macrolide, e.g., the compounds of formula(IA), (IB), (IC), (IE), (IF), (IIA), (IIB), (IIC), (IICa), (IIIA),(IIIB), (IVA), (IVB), (IVC), (IVD), (IVE), (VA), (VB), (VBa), (VC),(VIA), (VIB), (VIC), (VIIA), (VIIB), (VIIC), (VIID), (VIIE), (VIIF),(VIIG), (VIIIA), (VIIIB), (VIIIC), or (VIIID).

Oxidizing Agents Capable of Converting an Alcohol to a Carbonyl Group

Oxidizing agents capable of converting an alcohol to a carbonyl groupare known in the art. Non-limiting examples of these oxidizing agentsinclude Dess-Martin periodinane, TEMPO (in the presence of bleach orBAIB), a dimethylsulfonium compound (e.g., dimethylchlorosulfoniumchloride), aluminum trialkoxide with an excess of a ketone (e.g.,acetone), and catalytic tetrapropylammonium perruthenate (TPAP) (in thepresence of N-methylmorpholine oxide). The dimethylsulfonium compoundcan be prepared in situ under the conditions known for Parikh-Doeringoxidation, Swern oxidation, Corey-Kim oxidation, or Pfitzner-Moffattoxidation. An oxidation reaction of an alcohol to a carbonyl group(e.g., a ketone) can be performed using aluminum trialkoxide and anexcess of a ketone (e.g., acetone) under the conditions known in the artfor Oppenauer oxidation. Allylic and benzylic alcohols can also beoxidized with MnO₂.

Reducing Agents

Reducing agents that can be used in the methods of the invention arethose known in the art. A reducing agent can be an electron-transferreducing agent, a metal hydride, or a metalloid hydride. Non-limitingexamples of electron-transfer reducing agent include alkali metals inoxidation state (0), alkali earth metals in oxidation state (0), alkaliarenides, lanthanide (II) salts (e.g., SmI₂), Zn(0), Fe(0), and Mn(0).

Non-limiting examples of metal hydrides and metalloid hydrides includeboron hydride compounds (e.g., NaBH₄, LiBH₄, LiB(Et)₃H, selectrides(e.g., L-selectride), and boranes (e.g., 9-BBN and alpine borane)),aluminum hydride compounds (e.g., LiAlH₄, Red-Al®, and alanes (e.g.,DIBAL)), hydrosilanes (e.g., PMHS and Ph₂SiH₂), hydrostannanes (e.g.,Bu₃SnH), copper hydride complexes (e.g., Stryker's reagent), palladiumhydride complexes, platinum hydride complexes, iridium hydridecomplexes, rhodium hydride complexes, and ruthenium hydride complexes.Reducing agents can be formed in situ, e.g., a copper hydride complexcan be formed by a reaction of a copper salt with, e.g., a boron hydridecompound or a hydrosilane. Thus, some reducing reagents (e.g., boronhydride compounds, hydrosilanes, and hydrostannanes) can be used incombination with a catalytic quantity of a metal salt (e.g., Cu, Pd, Pt,Ir, Rh, or Ru salt). Alternatively, catalytic reducing agents can bemetal salts (e.g., aluminum isopropoxide or a ruthenium complex) incombination with an alcohol, which undergo transfer hydrogenation ofcarbonyl-containing compounds without intermediacy of a metal hydride.Non-limiting examples of transfer hydrogenation reactions includeMeerwein-Ponndorf-Verley reduction (e.g., using aluminumisopropoxide/isopropanol) and Ru-catalyzed transfer hydrogenation (e.g.,Hashiguchi et al., J. Am. Chem. Soc., 117:7562-7563, 1995).

When a substrate is an α,β-unsaturated carbonyl compound (e.g., anα,β-enone), a reducing agent can be a 1,2-reducing agent or a1,4-reducing agent. For example, a reaction between an α,β-unsaturatedcarbonyl compound and a 1,2-reducing agent can afford, e.g., an allylicalcohol (or an allylic amine, if the starting compound is an enamide),whereas a reaction between an α,β-unsaturated carbonyl compound and a1,4-reducing agent can afford an α,β-saturated compound and can leavethe carbonyl group intact after work up of the reaction mixture.Non-limiting examples of 1,2-reducing agents include metal hydrides andmetalloid hydrides, e.g., aluminum hydride compounds, boron hydridecompounds (e.g., CeCl₃ with NaBH₄), and ruthenium hydride complexes.Non-limiting examples of 1,4-reducing agents include boron hydridecompounds, hydrostannanes, copper hydride complexes (e.g., Stryker'sreagent), palladium hydride complexes, platinum hydride complexes,iridium hydride complexes, rhodium hydride complexes, and rutheniumhydride complexes.

A compound having an allylic leaving group (e.g., a carboxylate, ahalide, or a sulfonate) can be treated with an allylic reducing agent toreplace the leaving group with a hydrogen atom. A non-limiting exampleof allylic reducing agent is a palladium salt in combination with aformic acid salt (e.g., trialkylammonium formate).

Hydroxyl Protecting Groups and Hydroxyl Protecting Group Removing Agents

Hydroxyl protecting groups can be as defined herein. In particular, ahydroxyl protecting group can be an acyl, a sulfonyl, an arylalkyl(e.g., benzyl or p-methoxybenzyl), an aryl (e.g., p-methoxyphenyl), oran optionally substituted silyl (e.g., TMS, TES, TBS, TIPS, TBDPS, DMPS,or TPS). Hydroxyl protecting groups, hydroxyl protecting agents, andhydroxyl protecting reaction conditions can be selected to protectselectively certain hydroxyl groups in a compound, while leaving otherhydroxyl groups unprotected. The choice of hydroxyl protecting groupsfor a compound can facilitate subsequent deprotection strategies, assome hydroxyl protecting groups can be removed in the presence of othersusing appropriate hydroxyl protecting group removing agents. Some ofthese strategies involving the choice of silyl hydroxyl protectinggroups are discussed in, e.g., Silicon-Based Blocking Agents, Gelest,Inc., 2011.

Hydroxyl protecting group removing agents are those agents that canreact with a compound having a protected hydroxyl group to afford thecompound with a deprotected hydroxyl group. Hydroxyl protecting groupremoving agents and deprotection reaction conditions can be those knownin the art. In a non-limiting example, hydroxyl masked as silyl ethercan be unmasked by a reaction with a fluoride source (e.g., a fluoridesalt, such as KF or TBAF). Alternatively, hydroxyl protected as TMS orTES ether can be deprotected by a reaction with a Brønsted acid (e.g., acarboxylic acid). In another non-limiting example, hydroxyl protected asan ester can be deprotected by a reaction with a C₁₋₆ alkoxide (e.g.,alkali C₁₋₆ alkoxide or alkali earth C₁₋₆ alkoxide). In yet anothernon-limiting example, hydroxyl protected as an arylalkyl ether (e.g.,1-arylalk-1-yl ether) can be deprotected using a reduction reaction,e.g., with Pd/C and H₂ or with Na/NH₃. Alternatively, hydroxyl protectedas an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by areaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In stillanother non-limiting example, hydroxyl protected as alkoxyalkyl ether(e.g., 1-alkoxyalk-1-yl) or THP ether can be deprotected by a reactionwith a Brønsted acid. Cyclic protected diols, such as acetals or ketals(e.g., as 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane,2-alkyl-1,3-dioxane, or 2,2-dialkyl-1,3-dioxane), can be deprotected bya reaction with a Brønsted acid (e.g., a carboxylic acid).

Dihydroxylation and Oxidative Carbon-Carbon Bond Cleavage

Dihydroxylation reaction produces diols from olefins. The reactionconditions can be those known in the art. Dihydroxylation reaction maybe direct (e.g., Sharpless dihydroxylation, Upjohn dihydroxylation, orMilas dihydroxylation) or indirect (e.g., throughepoxidation/hydrolysis, diborylation/oxidation, orcarboxylation/hydrolysis (e.g., Woodward reaction or Prévost reaction)).A direct dihydroxylation reaction can be performed using an osmiumcomplex (e.g., OsO₄ or osmate salt). A catalytic quantity of the osmiumcomplex can be used in the dihydroxylation reactions in combination withan additional oxidizing agent (e.g., N-methylmorpholine N-oxide orhydrogen peroxide). The dihydroxylation reaction can be renderedstereoselective by including a chiral ligand (e.g., in AD-mix, which isa mixture of osmate and a chiral ligand).

When a dihydroxylation reaction is performed with an osmium complex anda periodate salt as oxidizing agent, the carbon-carbon double bond of anolefin can be cleaved to afford two carbonyl groups. The transformationof an olefin to two carbonyl groups is referred to herein as a cleavagereaction. Cleavage reaction conditions can be those known in the art.Non-limiting examples of cleavage reaction conditions can be ozonolysisreaction conditions or a reaction with an osmium complex (e.g., OsO₄ orosmate salt) and a periodate salt. A vicinal diol can be cleaved bysodium periodate or potassium permanganate.

Epimerizations

Epimerization reactions can be used to invert a stereogenic centerhaving an undesired stereochemical identity. For example, throughepimerization, R stereogenic center can be converted to S stereogeniccenter and vice versa. Epimerization of a stereogenic sp³-carbon bondedto one hydrogen atom and to one hydroxyl group can be achieved through areaction sequence involving oxidation of the hydroxyl group to acarbonyl group followed by a 1,2-reduction reaction. The 1,2-reductionreaction can provide the desired stereochemical identitydiastereoselectively, or the reaction can be carried out using a chiralcatalyst, chiral auxiliary, or a chiral reducing agent. Non-limitingexamples of chiral reducing agents include alpine borane and prapineborane. Non-limiting examples of 1,2-reduction reactions involvingchiral catalysts are Corey-Bakshi-Shibata reduction, Noyorihydrogenation, and Noyori transfer hydrogenation, Theoxidation/reduction reaction sequence can be carried out in situ usingdynamic kinetic resolution. A dynamic kinetic resolution can furtherinvolve a reaction with a hydroxyl protecting agent, which removes thedesired stereoisomer from the reduction/oxidation equilibrium. In anon-limiting example, a dynamic kinetic resolution of chiral secondaryalcohols can involve reduction/oxidation equilibration usingη⁵-Ph₅CpRu(CO)₂H in combination with enantioselective esterificationusing isopropenyl acetate catalyzed by a lipase enzyme (e.g., lipase Bfrom Candida Antarctica, see, e.g., Martin-Matute et al., J. Am. Chem.Soc., 127:8817-8825, 2005).

Epimerization can also be carried out on a compound containing atetrahydropyran-2-yl-acetaldehyde moiety, in which carbon 2 of the pyranring exhibits an undesired stereochemical identity. Contacting thiscompound with L-proline can provide equilibrium between twostereoisomers. If other, non-equilibrating stereogenic centers arepresent in the compound, the most stable stereoisomer will be present ina larger quantity relative to other stereoisomer(s) in equilibrium withthe most stable stereoisomer.

The following examples are meant to illustrate the invention. They arenot meant to limit the invention in any way.

EXAMPLES Example 1—C.2-C.3 Macrocyclization ThroughHorner-Wadsworth-Emmons Olefination

A halichondrin macrolide 3 can be prepared according to the belowsequence.

Compound 1 can be converted to compound 2 through theHorner-Wadsworth-Emmons olefination (e.g., under Masamune conditions oraccording to Helquist protocol). Compound 2 can be converted to compound3 after global deprotection (e.g., removal of silyl groups with afluoride source, such as TBAF).

Example 2—C.2-C.3 Macrocyclization Through Ring-Closing OlefinMetathesis

A halichondrin macrolide 3 was prepared according to the below sequence.

Ring-Closing Olefin Metathesis

Compound 4 (0.047 g, 0.027 mmol) was dissolved in toluene (57.0 mL) and1,4-benzoquinone (1 mg, 10 μmol), and Hoveyda-Grubbs 2nd generationcatalyst (3 mg, 5.3 μmol) was added. The reaction mixture was warmed to70° C. Upon completion (2 h), DMSO (9.51 μL, 0.134 mmol) was added, andthe solution was allowed to stir at room temperature for 16 h. Afterconcentration, the resulting green residue was purified by columnchromatography (Biotage Ultra cartridge, 10 g, heptane/EtOAc) to providetwo RCM adducts, 5-cis and 5-trans with cis impurity (19 mg total, 0.011mmol, 41%, 3:1 ratio cis/trans). 5-cis: ¹H NMR (400 MHz, BENZENE-d₆)δ=7.97-7.88 (m, 2H), 7.80 (dd, J=2.9, 6.4 Hz, 2H), 7.76-7.66 (m, 4H),7.28-7.17 (m, 12H), 6.66-6.55 (m, 1H), 6.04 (d, J=15.6 Hz, 1H), 5.30(dd, J=3.7, 6.8 Hz, 1H), 5.02 (s, 1H), 4.92 (t, J=1.0 Hz, 1H), 4.89 (br.s., 1H), 4.87 (s, 1H), 4.77-4.73 (m, 1H), 4.77-4.73 (m, 1H), 4.75 (s,1H), 4.65 (br. s., 1H), 4.47 (br. s., 1H), 4.20 (dd, J=3.7, 6.8 Hz, 1H),4.16-4.09 (m, 2H), 4.03-3.89 (m, 3H), 3.80-3.66 (m, 3H), 3.43 (d, J=9.4Hz, 4H), 3.33 (d, J=3.5 Hz, 1H), 3.22 (d, J=9.4 Hz, 1H), 2.96-2.90 (m,1H), 2.85-2.75 (m, 1H), 2.63-2.44 (m, 1H), 2.31 (d, J=5.5 Hz, 1H),2.25-1.97 (m, 2H), 1.96-1.57 (m, 1H), 1.52-1.23 (m, 1H), 1.21 (s, 1H),1.15-1.13 (m, 1H), 1.08 (s, 1H), 1.15 (s, 1H), 0.99-0.97 (m, 1H), 0.93(s, 1H), 0.85-0.85 (m, 1H), 0.85 (s, 1H), 0.92 (s, 1H), 0.81 (br. s.,1H), 0.39 (s, 1H), 0.32-0.30 (m, 1H), 0.30 (s, 1H), 0.30-0.29 (m, 1H),0.30 (s, 1H), 1.21 (s, 9H), 1.14 (s, 9H), 1.13-1.12 (m, 3H), 1.08 (s,9H), 0.98 (s, 9H), 0.97-0.95 (m, J=2.0 Hz, 3H), 0.93 (s, 9H), 0.85 (s,9H), 0.30 (s, 3H), 0.30 (s, 3H), 0.18 (s, 3H), 0.14 (s, 3H), 0.13 (s,3H), 0.11 (s, 3H), 0.01 (s, 3H), −0.11 (s, 3H)

Compound 3

The mixture of compounds 5-cis and 5-trans (0.019 g, 0.011 mmol) wasdissolved in N,N-dimethylacetamide (0.304 mL, 3.27 mmol). Imidazolehydrochloride (5.76 mg, 0.055 mmol) and TBAF (0.110 mL, 0.11 mmol) wereadded, and the reaction monitored by LCMS. Upon completion, water (5 mL)was added. Extraction with heptane removed lypophilic impurities. Theaqueous layer was then extracted with toluene (5 mL) followed bytoluene/THF (3:1 v/v, 4×8 mL). Brine was added to the aqueous layer toassist the recovery after the third extraction. The organic layers werecombined and washed with saturated NaCl (2×6 mL). The organic layerswere then dried over MgSO₄, filtered, and concentrated. The colorlessresidue was azeotroped with acetonitrile/water (3:1, v/v) at 30° C. toprovide compound 6 (27 mg, 310% mass recovery) as a pale tan solid thatwas used directly in the next step. LCMS (Cl): calcd. 790, found, Na ion813 (M+1+22(Na)). Crude 6 was dissolved in DCM (0.087 mL, 1.352 mmol),and PPTS (0.028 g, 0.11 mmol) was added. The reaction was monitored byLCMS. At 2 h, product forms as determined by M+1 of 773.

The residue (8.70 mg, 11.00 μmol) was dissolved in dichloromethane (0.5mL) at ambient temperature and PPTS (18 mg, 72 μmol) was added. Thereaction mixture was filtered through a SiO₂ plug (0.75 cm×2 cm) usingEtOAc/MeOH to provide 5.5 mg of residue after concentration. Thestructure was confirmed by LCMS comparison with an authentic standard.

UPLC column: Waters Acquity UPLC HSS T3 1.8 μm, 2.1*50 mm, Part no.186003538, Serial no. 01753602015820 Temperature: 50° C. Flow rate: 0.8mL/min Gradient: Time, min %-Solvent A %-Solvent B Initial 97 3 0.1 97 32.0 1 99 2.5 1 99 2.51 97 3 3.0 97 3 Injection volume: 1 μL UVDetection: PDA 210-400 nm Mass ES(+), mass scan 100.00 to 2000.00Detection(SQD): Run time: 3 min

Compound 3 standard, RT 1.90 min, ES+(M+1) 773

Found, RT 1.90 min, ES+(M+1) 773.

Compound 4 was prepared according to the below sequence:

(6S,E)-6-((2S,3R,4S,5S,6S)-6-(but-3-en-1-yl)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-((4-methoxybenzyl)oxy)-4-methyloctahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)hex-4-en-3-ol

Compound 8 (0.200 g, 0.242 mmol) and compound 7 (0.175 g, 0.156 mmol)were dissolved in N₂ sparged THF (0.5 mL). In a separate flask, theligand (0.255 g, 0.86 mmol) and chromium(II) chloride (0.106 g, 0.862mmol) were suspended in N₂ sparged THF (1.5 m) at 30° C. Triethylamine(0.12 mL, 0.861 mmol) was added, and the green solution was stirred for30 minutes before cooling to 0° C., at which time, Ni-DMP complex (8.00mg, 0.024 mmol) was added. The solution of compounds 7 and 8 was added,and the reaction warmed to room temperature. Upon completion, thereaction was cooled to 0° C., and ethylenediamine (0.158 ml, 2.345 mmol)was added and the stirred for 1 h. Water (2 mL) was added followed byheptane (10 mL) after 10 min. The phases were separated, and the aqueousphase was extracted with MTBE twice. The combined extracts weresequentially washed with HCl (1 N), water, and brine. After drying withMgSO₄, the filtrates were concentrated to provide a pale green solid.Heptane trituration provided a solution that was loaded directly on aRedisep cartridge (4 g, heptane/EtOAc) and provided the compound 9 (217mg, 0.119 mmol, 76%, (est. 3:1 ratio of diastereomers)). The product wasused without further purification in the next step.

(S,E)-6-((2S,3R,4S,5S,6S)-6-(but-3-en-1-yl)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-((4-methoxybenzyl)oxy)-4-methyloctahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)hex-4-en-3-one

Compound 9 (0.217 g, 0.119 mmol) was dissolved in DCM (2.170 mL), andwater (0.107 μL) was added followed by Dess-Martin periodinane (0.061 g,0.143 mmol). Upon completion, aqueous sodium bicarbonate (2 mL) wasadded, and the mixture was stirred for 15 minutes before extracting withDCM (3×2 mL). The combined extracts were washed with water and dried(Na₂SO₄) to provide 246 mg of crude product as a white foam. Thematerial was purified using a Redisep cartridge (4 g, conditioned with9:1::heptane/EtOAc, loaded with 1:1 heptane/DCM, and eluted as a single30 mL fraction of heptane/EtOAc (9:1, (v/v)). After concentration, 15(211 mg, 0.116 mmol, 97%) was provided as a white crunchy foam. ¹H NMR(400 MHz, CDCl₃) δ=d=7.92-7.84 (m, 2H), 7.79 (dd, J=2.9, 6.4 Hz, 2H),7.77-7.70 (m, 4H), 7.34-7.16 (m, 14H), 6.78 (d, J=1.0 Hz, 2H), 6.62 (d,J=1.0 Hz, 1H), 5.96-5.81 (m, 1H), 5.88 (d, J=5.9 Hz, 1H), 5.39-5.30 (m,1H), 5.35 (dd, J=4.1, 6.8 Hz, 1H), 5.11-5.03 (m, 1H), 5.12-5.02 (m, 1H),4.96 (d, J=10.9 Hz, 1H), 5.00-4.92 (m, 1H), 4.85 (s, 1H), 4.82-4.79 (m,1H), 4.79-4.76 (m, 1H), 4.79 (d, J=8.2 Hz, 1H), 4.50 (t, J=5.5 Hz, 1H),4.40 (d, J=7.8 Hz, 1H), 4.25-4.19 (m, 1H), 4.18-4.11 (m, 1H), 4.11-4.00(m, 1H), 3.96 (dd, J=5.1, 9.4 Hz, 1H), 3.85-3.67 (m, 1H), 3.61-3.41 (m,2H), 3.34-3.25 (m, 3H), 3.20-3.10 (m, 2H), 2.85-2.57 (m, 1H), 2.55-2.30(m, 2H), 2.28-1.89 (m, 7H), 1.89-1.76 (m, 4H), 1.76-1.28 (m, 3H), 1.18(s, 7H), 1.24-1.16 (m, 6H), 1.15 (s, 1.0H), 1.09 (s, 9H), 0.97 (s, 11H),0.96 (br. s., 4H), 0.93 (s, 9H), 0.91 (s, 9H), 0.85 (t, J=6.8 Hz, 4H),0.33 (br. s., 3H), 0.32 (br. s., 3H), 0.19-0.17 (m, 3H), 0.14 (br. s.,3H), 0.14-0.13 (m, 3H), 0.12 (s, 6H), 0.07-0.05 (m, 3H), 0.07-0.05 (m,3H), 0.01-−0.03 (m, 1H), −0.01 (s, 3H).

(S,E)-6-((2R,3R,4S,5S,6S)-6-(but-3-en-1-yl)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-hydroxy-4-methyloctahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)hex-4-en-3-one

Compound 10 (0.211 g, 0.116 mmol) was dissolved in DCM (4.22 mL), t-BuOH(0.042 mL) and pH 7 phosphate buffer were added (0.422 mL). DDQ (53 mg,0.23 mmol) was added. Upon completion, aqueous sodium bicarbonate (10mL) was added, and the solution stirred for 10 minutes before it wasextracted with heptane (3×5 mL). The combined extracts were washed withaqueous sodium bicarbonate and water before drying with Na₂SO₄. Thefiltrate was concentrated, and residue was purified by columnchromatography (Biotage Ultra cartridge, 10 g, heptane/EtOAc) to provide16 (139 mg, 0.083 mmol, 70%). ¹H NMR (400 MHz, BENZENE-d6) δ=7.93-7.84(m, 2H), 7.84-7.67 (m, 7H), 7.34-7.14 (m, 11H), 6.62 (d, J=1.0 Hz, 1H),5.96-5.82 (m, 1H), 5.35 (dd, J=4.3, 7.4 Hz, 1H), 5.08 (d, J=15.6 Hz,1H), 4.97 (d, J=0.2 Hz, 2H), 4.92 (s, 2H), 4.89 (s, 3H), 4.86 (s, 3H),4.75 (s, 3H), 4.48-4.34 (m, 2H), 4.25-4.18 (m, 1H), 4.16 (s, 1H),4.13-4.07 (m, 1H), 4.07-3.95 (m, 2H), 3.95-3.85 (m, 1H), 3.85-3.75 (m,1H), 3.75-3.60 (m, 3H), 3.52-3.42 (m, 4H), 3.33-3.26 (m, 1H), 3.12-3.08(m, 1H), 2.86-2.72 (m, 2H), 2.72-2.58 (m, 3H), 2.54-2.00 (m, 11H),1.98-1.20 (m, 11H), 1.12 (s, 9H), 1.28-1.11 (m, 60H), 1.10 (s, 9H), 0.98(s, 9H), 0.93-0.91 (m, 3H), 0.87 (s, 9H), 0.85 (s, 9H), 0.83 (s, 9H),0.33 (br. s., 3H), 0.32 (br. s., 3H), 0.18 (s, 3H), 0.15 (s, 3H), 0.14(br. s., 3H), 0.12 (s, 3H), 0.06 (s, 3H), −0.01 (s, 3H)(2S,3R,4S,4aS,6R,7R,8aS)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-((S,E)-6-((2R,3R,4S,5S,6S)-6-(but-3-en-1-yl)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-3-oxohex-4-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-7-((tert)-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyloctahydropyrano[3,2-b]pyran-3-yl)acrylate

Compound 11 (0.082 g, 0.048 mmol) was dissolved in DCM (820 μL), and theresulting solution was cooled to 0° C. Triethylamine (0.05 mL, 0.359mmol) was added, followed by acryoyl chloride (4 μL, 0.049 mmol).Additional 0.05 mL TEA and 6 μL acryoyl chloride were added. Uponcompletion of the reaction, saturated sodium bicarbonate (5 mL) wasadded, and the reaction mixture was extracted with heptane (3×3 mL). Thecombined extracts were washed with water and dried (Na₂SO₄). Afterconcentration, the residue was purified by column chromatography(Biotage Ultra cartridge, 10 g, heptane/EtOAc) to provide compound 4 (48mg, 0.027 mmol, 57%) and a mixture of compounds 16 and 17 (35 mg). ¹HNMR (400 MHz, BENZENE-d₆) δ=7.95-7.86 (m, 3H), 7.79 (dd, J=3.1, 6.6 Hz,3H), 7.73-7.66 (m, 7H), 7.34-7.27 (m, 1H), 7.26-7.15 (m, 7H), 6.66-6.57(m, 1H), 6.34 (dd, J=1.6, 17.6 Hz, 1H), 5.99 (dd, J=10.2, 17.2 Hz, 1H),5.94-5.80 (m, 1H), 5.35 (dd, J=4.1, 7.2 Hz, 1H), 5.31-5.25 (m, 1H),5.15-4.92 (m, 1H), 4.91-4.83 (m, 3H), 4.77 (s, 1H), 4.51-4.41 (m, 1H),4.34 (t, J=1.0 Hz, 1H), 4.25-4.19 (m, 1H), 4.16 (s, 1H), 4.09-3.95 (m,4H), 3.89 (dt, J=4.7, 9.4 Hz, 1H), 3.80 (t, J=8.8 Hz, 1H), 3.75-3.68 (m,1H), 3.66 (br. s., 2H), 3.60-3.49 (m, 1H), 3.42-3.35 (m, 2H), 3.29 (d,J=1.0 Hz, 1H), 2.95 (t, J=1.6 Hz, 1H), 2.86-2.61 (m, 2H), 2.56-2.33 (m,3H), 2.31-1.34 (m, 15H), 2.30-2.00 (m, 2H), 1.12 (s, 9H), 1.09 (s, 9H),1.06 (d, J=1.0 Hz, 3H), 0.97 (s, 9H), 0.95 (d, J=1.0 Hz, 3H), 0.93 (s,97H), 0.91 (s, 9H), 0.85 (s, 9H), 0.32 (br. s., 3H), 0.18 (s, 3H), 0.14(s, 3H), 0.13 (br. s., 3H), 0.12 (s, 3H), 0.07-0.05 (m, 3H), 0.06 (s,3H), −0.01 (s, 3H)

Compound 8 was prepared as shown in the following sequence:

(2S,3S,4S,5R,6S)-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)-2-(3-hydroxypropyl)tetrahydro-2H-pyran-3-ylbenzoate

Compound 15 (1.160 g, 1.548 mmol) was dissolved in THF (10 mL), and9-borabicyclo[3.3.1]nonane (5.0 mL, 2.50 mmol) was added. Uponcompletion, the solution was cooled to 0° C., and water (10 mL) wasadded followed by sodium perborate tetrahydrate (1.429 g, 9.288 mmol).The mixture was stirred for 12 h. Aqueous sodium bicarbonate was added,and the mixture was extracted twice with heptane/MTBE (1:1 (v/v)). Thecombined organic layers were washed with aqueous sodium bicarbonatefollowed by water and then dried over sodium sulfate. The resultingsolution was concentrated, and the resulting residue was purified bycolumn chromatography to provide 0.820 g (1.13 mmol, 73%) of compound8A. ¹H NMR (400 MHz, CDCl₃) δ=8.09 (br. s., 1H), 7.44-7.36 (m, 1H),7.27-7.22 (m, 2H), 7.18-7.13 (m, 2H), 5.96 (br. s., 1H), 5.21 (br. s.,1H), 4.47 (br. s., 1H), 4.11 (br. s., 2H), 4.01-3.91 (m, 3H), 3.65 (br.s., 3H), 3.30 (br. s., 1H), 0.96 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H),0.16-0.08 (m, 27H).

(2S,3S,4S,5R,6S)-2-(3-acetoxypropyl)-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-ylbenzoate

Compound 8A (0.870 g, 1.134 mmol) was dissolved in DCM (8.70 ml) andcooled to 0° C. Triethylamine (1 mL, 7.175 mmol) and DMAP (0.014 g,0.113 mmol) were added followed by Ac₂O (0.214 mL, 2.268 mmol). Uponcompletion, saturated aqueous sodium bicarbonate (30 mL) was added. Themixture was extracted with MTBE (3×20 mL). The combined extracts werewashed with saturated aqueous sodium bicarbonate, then water, and thenbrine. After drying over Na₂SO₄, the solution was concentrated toprovide compound 8B (0.895 g, 1.106 mmol, 98%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ=8.12-8.04 (m, 1H), 7.55-7.48 (m, 1H), 7.43-7.34(m, 2H), 6.49-6.44 (m, 1H), 5.97-5.89 (m, 1H), 5.18-5.09 (m, 1H),4.46-4.33 (m, 1H), 4.14-4.01 (m, 3H), 3.96-3.89 (m, 2H), 3.20 (s, 3H),3.00-2.97 (m, 1H), 2.35-2.33 (m, 1H), 2.06-1.99 (m, 2H), 1.81-1.74 (m,1H), 1.64-1.54 (m, 2H), 0.96 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H),0.18-0.08 (m, 9H), 0.07 (s, 6H), 0.04 (s, 6H), −0.05-−0.11 (m, 23)

(2S,3S,4S,5R,6S)-2-(3-acetoxypropyl)-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3-ylbenzoate

Compound 8B (0.895 g, 1.106 mmol) was dissolved in toluene (5.37 ml) andacetonitrile (10.74 mL, 205.633 mmol). t-Butyldimethylchlorosilane(0.017 g, 0.111 mmol) was added, and the solution was warmed to 30° C.NIS (1.990 g, 8.846 mmol) was added. Upon completion, the reactionmixture was poured into a solution of sodium thiosulfate (2 g) insaturated aqueous sodium bicarbonate (40 mL). MTBE (20 mL) was added,and the mixture stirred for 45 minutes. The MTBE layer was removed invacuo, and the aqueous layer was extracted with MTBE (2×20 mL). Thecombined MTBE extracts were washed with 10% (w/v) aqueous sodiumthiosulfate, followed by water and then by brine. The solution was driedover MgSO₄ and concentrated to provide crude 8C (857 g, 0.993 mmol, 90%)as pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=8.06 (br. s., 2H), 7.53(br. s., 1H), 7.40 (br. s., 2H), 6.73 (br. s., 1H), 6.38 (d, J=14.8 Hz,1H), 5.20 (br. s., 1H), 5.01 (br. s., 1H), 4.67-4.56 (m, 1H), 4.54-4.46(m, 1H), 4.44-4.36 (m, 1H), 4.17-3.98 (m, 3H), 3.98-3.82 (m, 2H),3.34-3.19 (m, 1H), 2.72 (s, 1H), 2.33 (s, 1H), 2.14-1.88 (m, 3H),1.88-1.50 (m, 4H), 1.37-1.17 (m, 2H), 0.94 (s, 9H), 0.88 (s, 9H), 0.87(s, 10H), 0.05 (s, 18H)

(2S,3S,4S,5R,6S)-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-2-(3-hydroxypropyl)tetrahydro-2H-pyran-3-ol

Compound 8C (0.814 g, 0.943 mmol) was dissolved in toluene (8.14 mL) andcooled to −10° C. DIBAL (4.72 ml, 4.716 mmol) was added. After 15minutes, methanol (0.191 mL, 4.716 mmol) was added followed by aqueousHCl (0.1 N, 20 mL). The mixture was stirred for 15 minutes and theextracted with MTBE three times. The combined extracts were washed withwater and brine before drying over Na₂SO₄. The resulting solution wasconcentrated in vacuo, and the residue was purified by columnchromatography (Biotage Ultra cartridge, 25 g; heptane/EtOAc) to providecompound 8D (601 g, 0.838 mmol, 89%).

(2S,3S,4S,5R,6S)-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-2-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-3-ol

Step 1. Compound 8D (0.601 g, 0.838 mmol) in DCM (6.01 mL) was cooled to0° C. 2,4-Lutidine (0.291 mL, 2.515 mmol) was added followed bychlorotriethylsilane (0.148 mL, 0.88 mmol). Upon completion, saturatedaqueous sodium bicarbonate (20 mL) was added, and the mixture wasextracted with DCM (3×20 mL). The combined extracts were washed withwater. After drying over Na₂SO₄, the organic layers were concentrated toprovide crude TES-ether (0.697 g).

Step 2. The TES-ether (0.697 g) was dissolved in DCM (6.97 mL) andcooled to 0° C. 2,4-Dimethylpyridine (0.388 mL, 3.354 mmol) was addedfollowed by t-butyldimethylsilyl trifluoromethanesulfonate (0.231 mL,1.006 mmol). Upon completion, saturated aqueous sodium bicarbonate (20mL) was added, and the mixture was extracted with MTBE (3×20 mL). Thecombined extracts were washed with water, HCl (0.1 N), water, and thenaqueous sodium bicarbonate. After drying, the filtrate was concentratedto a colorless oil and purified by column chromatography (Biotage Snap25 cartridge, heptane/EtOAc) to provided compound 8E (0.650 g, 0.687mmol, 82%). ¹H NMR (400 MHz, CDCl₃) δ=6.80-6.57 (m, 1H), 6.26 (dd,J=0.8, 14.5 Hz, 1H), 4.58-4.25 (m, 1H), 3.92-3.66 (m, 3H), 3.64-3.55 (m,3H), 3.05 (d, J=8.6 Hz, 1H), 1.68-1.55 (m, 1H), 1.51-1.38 (m, 1H),1.49-1.33 (m, 2H), 1.00-0.83 (m, 36H), 0.60 (q, J=8.2 Hz, 6H),0.13-−0.03 (m, 33H)

(((2S,3R,4S,5S,6S)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(tert-butyldimethylsilane)

Step 1 (Swern oxidation): DMSO (0.19 mL, 1.685 mmol) in DCM (0.4 mL) wasadded to oxalyl chloride (2 M in DCM, 0.357 mL, 0.715 mmol) in DCM (1mL) at −78° C. After 10 minutes, a solution of compound 8E (0.169 g,0.179 mmol) in DCM (1 mL with a 1 mL rinse) was added dropwise at −78°C. The solution was warmed to −40° C. and stirred for 30 min. Thesolution was cooled to −78° C. and triethylamine (0.299 mL, 2.145 mmol)was added. The reaction mixture was warmed to 0° C. and HCl (0.1 N) wasadded. The mixture was extracted with DCM three times. The organiclayers were combined, washed with water and then dried with Na₂SO₄.Concentration provided the aldehyde (171 mg, 134% mass recovery) as apale yellow oil that was used directly in step 2.

Step 2. (Wittig reaction): Methyltriphenylphosphonium bromide (0.255 g,0.715 mmol) was suspended in THF (1.6 mL) and cooled to 0° C.Butyllithium (2M in cyclohexane, 0.349 ml, 0.697 mmol) was added, andthe resulting solution was stirred for 30 min. The aldehyde was dissolveTHF (1.6 mL) and added to the ylide mixture. Upon completion, HCl (0.1N) was added and the mixture extracted with heptane (3×20 mL). Thecombined organics were washed with water followed by aqueous sodiumbicarbonate. After drying with Na₂SO₄, the filtrate was concentrated toprovide crude compound 8F (0.155 g, 0.217 mmol, 122% mass recovery,contaminated with PPh₃). ¹H NMR (400 MHz, CDCl₃) δ=6.70 (q, J=6.3 Hz,1H), 6.38-6.22 (m, 1H), 5.88-5.71 (m, 1H), 5.13-4.96 (m, 2H), 4.39-4.28(m, 1H), 3.78 (s, 3H), 3.69-3.62 (m, 2H), 3.06-3.01 (m, 1H), 2.21-2.01(m, 1H), 2.20-2.00 (m, 1H), 1.82-1.63 (m, 1H), 1.45-1.20 (m, 1H), 0.92(s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09(s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H)

(((2S,3S,4S,5R,6S)-2-(but-3-en-1-yl)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(tert-butyldimethylsilane)

Compound 8F (0.127 g, 0.178 mmol) was dissolved in dichloromethane(1.270 mL) and cooled to 0° C. 2,4-Dimethylpyridine (0.057 g, 0.534mmol) was added followed by t-butyldimethylsilyltrifluoromethanesulfonate (0.049 ml, 0.214 mmol). After 3 h, additional2,4-dimethylpyridine (0.4 mL) and t-butyldimethylsilyltrifluoromethanesulfonate (0.1 mL) were added. Upon completion, aqueoussodium bicarbonate was added, and the reaction was stirred for 15 min.The product was extracted with heptane (3×10 mL). The combined extractswere washed with water, HCl (1 N, 2×10 mL), and water. After drying withNa₂SO₄/MgSO₄, the filtrate was concentrated to provide a pale yellow oilthat was purified by column chromatography (Biotage Ultra cartridge, 10g, H/EtOAc) to provide compound 8 (141 mg, 0.17 mmol, 95% over 3-steps(Swern, Wittig, TBS-protection)).

Example 3—C.3-C.4 Macrocyclization Through Ring-Closing OlefinMetathesis

A halichondrin macrolide 3 can be prepared according to the belowsequence.

Compound 12 can be prepared according to the following sequence:

Example 4—C. 12-C. 13 Macrocyclization Through Ring-Closing OlefinMetathesis

A halichondrin macrolide 3 can be prepared according to the belowsequence.

Compound 21 can be converted to compound 22 through the catalyticring-closing olefin metathesis (e.g., with catalytic quantities ofHoveyda-Grubbs 2^(nd) generation catalyst). Compound 22 can be convertedto compound 3 after global deprotection (e.g., removal of silyl groupswith a fluoride source, such as TBAF).

Example 5—C. 15-C. 16 Macrocyclization Through Ring-Closing OlefinMetathesis

A halichondrin macrolide 3 can be prepared according to the belowsequence.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butydiphenysilyl)oxy)-2-(2-((triethysilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)aceticacid

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol(compound 23. 70 mg, 0.076 mmol) and TEMPO (1.187 mg, 7.597 μmol) weredissolved in toluene (2 mL) at ambient temperature. To the resultingsolution were added pH 7 phosphate buffer (1 mL), a solution of sodiumchlorite (42.9 mg, 0.38 mmol) in water (1 mL), and 4% bleach (a solutionof sodium hypochlorite in water) (0.012 mL, 7.597 μmol) slowly. Afterbeing stirred overnight, the reaction mixture was treated with sodiumbisulfite (63.2 mg, 0.608 mmol) and water (5 mL). The resulting mixturewas extracted twice with MTBE (10 mL each time). The combined organiclayers were washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄.

Filtration, concentration in vacuo, and purification by silica gelcolumn chromatography using a 25-66% gradient of ethyl acetate inn-heptane as eluent provided 54 mg of the target product as a white foamsolid. ¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm0.50-0.66 (m, 6H) 0.86-1.01 (m, 9H) 1.05-1.17 (m, 18H) 1.30-1.45 (m, 3H)1.55-1.65 (m, 1.5H) 1.68-1.79 (m, 1.5H) 1.87-1.99 (m, 1H) 2.09-2.25 (m,1.5H) 2.38 (d, J=5.5 Hz, 1H) 2.94 (dd, J=9.4, 4.3 Hz, 0.5H) 3.11 (dd,J=9.6, 6.4 Hz, 0.5H) 3.34 (t, J=4.9 Hz, 0.5H) 3.46-3.54 (m, 1H) 3.58 (t,J=4.7 Hz, 0.5H) 3.62-3.78 (m, 2H) 3.88 (t, J=6.3 Hz, 0.5H) 3.95-4.09 (m,1H) 4.16-4.25 (m, 2H) 4.26-4.42 (m, 1.5H) 4.95-5.18 (m, 2H) 5.71 (m,J=6.3 Hz, 1H) 7.27-7.45 (m, 12H) 7.64-7.77 (m, 8H)

((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-hydroxy-4-methyloctahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methylpivalate

A solution of2-((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-((4-methoxybenzyl)oxy)-4-methyloctahydropyrano[3,2-b]pyran-2-yl)acetaldehyde(compound 25; 340 mg, 0.347 mmol) and((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)methylpivalate (compound 26; 197 mg, 0.452 mmol) in dichloromethane (10 mL)was cooled to −37° C. Methoxyacetic acid (0.533 mL, 6.946 mmol) andBF₃.OEt₂ (0.132 mL, 1.042 mmol) were added, and the resulting solutionwas stirred for 3 h between −20 to −35° C. The reaction mixture was thentreated with sat. NaHCO₃ (15 mL) and extracted twice with MTBE (30.3 mLeach). The organic layers were combined, washed with 30% aqueous NaCl(15 mL), and dried over MgSO₄. Filtration, concentration in vacuo, andpurification by silica gel column chromatography using a 20-50% gradientof ethyl acetate in n-heptane as eluent provided 0.367 g of a mixture ofthe target product and byproducts, identified as compound 25 thatunderwent MPM deprotection and compound 26 that underwent TESdeprotection. Without further purification, the mixture was dissolved inTHF (7.5 mL). In another reactor, Pd(PPh₃)₄ (0.037 g, 0.032 mmol) andtriphenylphosphine (0.034 g, 0.128 mmol) were dissolved in THF (2 mL)and treated with formic acid (0.123 mL, 3.204 mmol) and triethylamine(0.447 mL, 3.204 mmol). The resulting solution was added to thesubstrate solution prepared above. After being stirred for 20 h at 60 to65° C., the reaction mixture was diluted with MTBE (20 mL) and washedwith sat. aq. NaHCO₃ (5 mL) and 30% aqueous NaCl (5 mL). The organiclayer was dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using a 20-100%gradient of ethyl acetate in n-heptane as eluent to give 98 mg of thetarget product. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.01 (s, 9H) 1.05 (s, 9H)1.10 (d, J=6.3 Hz, 3H) 1.13 (d, J=7.8 Hz, 3H) 1.20 (s, 9H) 1.28-1.37 (m,1H) 1.45-1.73 (m, 8H) 1.77-1.85 (m, 1H) 1.91-2.15 (m, 5H) 2.24-2.33 (m,1H) 2.37-2.47 (m, 1H) 2.63-2.74 (m, 1H) 3.22 (t, J=2.5 Hz, 1H) 3.29-3.38(m, 1H) 3.49 (d, J=8.2 Hz, 1H) 3.55-3.64 (m, 2H) 3.68 (d, J=2.0 Hz, 1H)3.72-3.82 (m, 3H) 3.91 (t, J=5.9 Hz, 1H) 4.01 (dd, J=11.7, 4.7 Hz, 1H)4.05-4.10 (m, 1H) 4.13 (dd, J=11.7, 4.7 Hz, 1H) 4.22-4.34 (m, 1H)4.41-4.52 (m, 1H) 4.77-4.84 (m, 2H) 4.90 (d, J=2.0 Hz, 1H) 4.99 (d,J=2.3 Hz, 1H) 7.28-7.44 (m, 12H) 7.60 (dq, J=8.1, 1.5 Hz, 4H) 7.66-7.69(m, 2H) 7.75-7.78 (m, 2H)

((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methylpivalate

((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4R,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-hydroxy-4-methyloctahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methylpivalate (compound 27; 98 mg, 0.093 mmol) was dissolved indichloromethane (5 mL) and treated with imidazole (31.5 mg, 0.463 mmol)and chlorotriethylsilane (0.047 mL, 0.278 mmol) at ambient temperature.After 15 h, the reaction was quenched with saturated aqueous NH₄Cl (27%(w/v)) (10 mL). The resulting mixture was extracted twice with MTBE (20mL). The combined organic layers were washed with 30% aqueous NaCl (5.0mL) and dried over MgSO₄. Filtration, concentration in vacuo, andpurification by silica gel column chromatography using a 10-50% gradientof ethyl acetate in n-heptane as eluent provided 94 mg of the targetproduct. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.65 (q, J=7.8 Hz, 6H) 0.97 (t,J=7.8 Hz, 9H) 1.02 (s, 9H) 1.04 (s, 9H) 1.06-1.10 (m, 6H) 1.20 (s, 9H)1.44-1.52 (m, 2H) 1.58-1.68 (m, 4H) 1.71-1.84 (m, 3H) 1.85-2.01 (m, 2H)2.07-2.23 (m, 2H) 2.35-2.45 (m, 1H) 2.63-2.75 (m, 1H) 3.18-3.28 (m, 2H)3.43-3.51 (m, 2H) 3.57-3.61 (m, 2H) 3.64-3.72 (m, 1H) 3.74-3.85 (m, 3H)4.01 (dd, J=11.7, 4.7 Hz, 1H) 4.12 (dd, J=11.3, 5.1 Hz, 1H) 4.23-4.31(m, 1H) 4.39-4.47 (m, 1H) 4.78 (s, 1H) 4.84 (br. s., 1H) 4.86 (br. s.,1H) 4.97 (s, 1H) 7.29-7.44 (m, 12H) 7.61-7.71 (m, 8H)

((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methanol

((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methylpivalate (compound 28; 94 mg, 0.08 mmol) was dissolved indichloromethane (3.0 mL) and cooled to −78° C. DIBAL in toluene (1.0 M,0.24 mL) was charged at this temperature. After being stirred for 1 hbetween −65 to −78° C., the reaction mixture was treated with MeOH (0.5mL) and a Rochelle's salt solution (5.0 mL). The resulting mixture waswarmed to ambient temperature and extracted with MTBE (15 mL). Theorganic layers were washed 30% aqueous NaCl (5.0 mL) and dried overMgSO₄. Filtration and concentration in vacuo provided the target product(86 mg), which was used in next step without further purification. ¹HNMR (400 MHz, CDCl₃) δ ppm 0.65 (q, J=8.1 Hz, 6H) 0.97 (t, J=7.8 Hz, 9H)1.02 (s, 9H) 1.04 (s, 9H) 1.06-1.10 (m, 6H) 1.45-1.52 (m, 2H) 1.58-1.69(m, 4H) 1.72-1.83 (m, 3H) 1.83-1.98 (m, 3H) 2.09-2.25 (m, 2H) 2.37-2.46(m, 1H) 2.56-2.65 (m, 1H) 3.18-3.27 (m, 2H) 3.43-3.53 (m, 3H) 3.55-3.64(m, 3H) 3.65-3.72 (m, 1H) 3.74-3.85 (m, 1H) 4.10-4.21 (m, 1H) 4.37-4.44(m, 1H) 4.78 (s, 1H) 4.84 (d, J=2.0 Hz, 1H) 4.86 (s, 1H) 4.97 (d, J=2.3Hz, 1H) 7.30-7.42 (m, 12H) 7.61-7.71 (m, 8H)

(E)-ethyl3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenysilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethysilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylate

To a solution of((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)methanol(compound 35; 86 mg, 0.079 mmol) in dichloromethane (3.0 mL) at ambienttemperature was added sodium bicarbonate (26.6 mg, 0.316 mmol) andDess-Martin periodinane (50.3 mg, 0.119 mmol). After being stirred for 2h, the reaction mixture was diluted with MTBE (20 ml) and treated with asaturated aqueous Na₂S₂O₃ solution (10 mL) and water (5.0 mL). Theresulting mixture was stirred for 0.5 h at ambient temperature, and thelayers were separated. The organic layer was washed with a saturatedaqueous NaHCO₃ solution (10 mL) twice and 30% aqueous NaCl (5.0 mL) anddried over MgSO₄. Filtration followed by concentration in vacuo gave thetarget product((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-carbaldehyde,80 mg) as an oil. Without further purification, the crude product wasdissolved in THF (4.0 mL) and cooled to 0° C. In an another reactionflask, ethyl 2-(diethoxyphosphoryl)acetate (73.7 μL, 0.368 mmol) wasdissolved in THF (2.7 mL), cooled to 0° C., and treated with 60% sodiumhydride (13.26 mg, 0.332 mmol). After 20 min at 0° C., the resultingsolution was added to the starting material reactor. After 30 min,saturated aqueous NH₄Cl (27% (w/v)) (8.0 mL), water (2.8 mL), and MTBE(20 mL) were added, and the resulting mixture was warmed to ambienttemperature. The layers were separated, and the aqueous layer wasextracted with MTBE (12 mL). The combined organic layers were washedwith 30% aqueous NaCl (10 mL) and dried over MgSO₄. Filtration,concentration in vacuo, and purification by silica gel columnchromatography using a 20-50% gradient of ethyl acetate in n-heptane aseluent provided 71 mg of the target product (compound 29). ¹H NMR (400MHz, CDCl₃) δ ppm 0.65 (q, J=8.1 Hz, 6H) 0.97 (t, J=8.2 Hz, 9H) 1.02 (s,9H) 1.04 (s, 9H) 1.06-1.10 (m, 6H) 1.45-1.52 (m, 2H) 1.57-1.70 (m, 5H)1.72-1.83 (m, 3H) 1.83-1.98 (m, 2H) 2.08-2.23 (m, 2H) 2.38-2.47 (m, 1H)2.76-2.86 (m, 1H) 3.18-3.28 (m, 2H) 3.43-3.51 (m, 2H) 3.56-3.62 (m, 2H)3.64-3.71 (m, 1H) 3.73-3.85 (m, 3H) 4.19 (q, J=7.3 Hz, 2H) 4.40-4.47 (m,1H) 4.60-4.69 (m, 1H) 4.78 (s, 1H) 4.86 (s, 2H) 4.98 (d, J=2.0 Hz, 1H)6.00 (dd, J=15.6, 1.6 Hz, 1H) 6.87 (dd, J=15.6, 5.1 Hz, 1H) 7.30-7.42(m, 12H) 7.61-7.71 (m, 8H)

(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol

To a solution of (E)-ethyl3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylate(compound 29; 71 mg, 0.061 mmol) in dichloromethane (4 mL), at −78° C.,was added a solution of DIBAL-H in toluene (1.0 M, 0.246 mL, 0.246mmol). After being stirred for 1 h between −65 to −78° C., the reactionmixture was treated with MeOH (0.5 mL) and a Rochelle's salt solution(5.0 mL). The resulting mixture was warmed to ambient temperature andextracted twice with MTBE (15 mL). The combined organic layers werewashed 30% aqueous NaCl (5.0 mL) and dried over MgSO₄. Filtration andconcentration in vacuo provided the target product (compound 36, 68 mg),which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ ppm 0.65 (q, J=8.1 Hz, 6H) 0.97 (t, J=8.2 Hz, 9H)1.02 (s, 9H) 1.04 (s, 9H) 1.06-1.10 (m, 6H) 1.45-1.52 (m, 2H) 1.57-1.70(m, 4H) 1.72-1.83 (m, 3H) 1.84-1.98 (m, 2H) 2.08-2.22 (m, 2H) 2.34-2.42(m, 1H) 2.68-2.76 (m, 1H) 3.20-3.28 (m, 2H) 3.43-3.50 (m, 2H) 3.56-3.62(m, 2H) 3.64-3.71 (m, 1H) 3.73-3.85 (m, 3H) 4.14 (br s, 2H) 4.40-4.43(m, 1H) 4.49 (q, J=6.6 Hz, 1H) 4.78 (s, 1H) 4.83 (d, J=1.9 Hz, 1H) 4.86(s, 1H) 4.97 (d, J=1.9 Hz, 1H) 5.70-5.76 (m, 1H) 5.83-5.89 (m, 1H)7.30-7.43 (m, 12H) 7.61-7.72 (m, 8H)

(((2R,3R,4aS,6S,7R,8S,8aS)-6-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(alkyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-8-methyl-7-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-3-yl)oxy)(tert-butyl)diphenylsilane

To a solution of(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-3-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol(compound 36, 68 mg, 0.061 mmol) in THF (2.0 mL) at 0° C. was addedsodium hydride (60% in oil, 6.1 mg, 0.15 mmol). The resulting slurry wasstirred at ambient temperature for 20 min. Allyl bromide (0.032 mL, 0.37mmol) and DMF (0.5 mL, 6.5 mmol) were then added. The resulting mixturewas stirred for 16 h at ambient temperature. Saturated aqueous NH₄Cl(27% (w/v)) (5.0 mL), water (1.0 mL), and MTBE (10 mL) were added. Thelayers were separated, and the aqueous layer was extracted with MTBE (10mL). The combined organic layers were washed with 30% aqueous NaCl (3.0mL) and dried over MgSO₄. Filtration and concentration in vacuo provided71 mg of the target product. Without further purification, the crudeproduct((((2R,3R,4aS,6S,7R,8S,8aS)-6-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-8-methyl-7-((triethylsilyl)oxy)octahydropyrano[3,2-b]pyran-3-yl)oxy)(tert-butyl)diphenylsilane)(72 mg) was dissolved in acetic acid (4.0 mL) and treated with water(1.0 mL) at ambient temperature. After 5 h, the reaction mixture wasconcentrated in vacuo. The resulting residue was purified by silica gelcolumn chromatography using a 20-33% gradient of ethyl acetate inn-heptane as eluent to give 54 mg of the target product (compound 30).¹H NMR (400 MHz, CDCl₃) δ ppm 1.00 (s, 9H) 1.04-1.06 (m, 9H) 1.08-1.15(m, 6H) 1.45-1.76 (m, 11H) 1.80 (br. s., 1H) 1.91-2.15 (m, 5H) 2.24-2.34(m, 1H) 2.36-2.45 (m, 1H) 2.67-2.76 (m, 1H) 3.22 (br. s., 1H) 3.33 (br.s., 1H) 3.49 (d, J=7.8 Hz, 1H) 3.55-3.65 (m, 2H) 3.68 (br. s., 1H)3.72-3.83 (m, 3H) 3.91 (t, J=5.9 Hz, 1H) 3.95-3.99 (m, 4H) 4.07 (q,J=5.6 Hz, 1H) 4.41-4.53 (m, 2H) 4.81 (br. s., 1H) 4.81-4.84 (m, 1H) 4.88(d, J=2.0 Hz, 1H) 4.98 (d, J=2.0 Hz, 1H) 5.18 (d, J=10.2 Hz, 1H) 5.27(dd, J=17.2, 1.6 Hz, 1H) 5.73 (dd, J=16.0, 5.1 Hz, 1H) 5.79 (dd, J=15.2,5.1 Hz, 1H) 5.85-5.97 (m, 1H) 7.30-7.43 (m, 12H) 7.57-7.79 (m, 8H)

(2S,3R,4S,4aS,6R,7R,8aS)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyloctahydropyrano[3,2-b]pyran-3-yl2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

To a solution of2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)aceticacid (compound 24, 66 mg, 0.071 mmol) in dichloromethane (2 mL) atambient temperature were added TEA (0.022 mL, 0.156 mmol),2-methyl-6-nitrobenzoic anhydride (26.8 mg, 0.078 mmol) and4-dimethylaminopyridine (3.17 mg, 0.026 mmol). After 10 min, theresulting solution was added to a solution of(2S,3R,4R,4aS,6R,7R,8aS)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyloctahydropyrano[3,2-b]pyran-3-ol(compound 30, 54 mg, 0.052 mmol) in dichloromethane (1.0 ml). Afterbeing stirred overnight, the reaction mixture was treated with asaturated aqueous NH₄Cl solution (5.0 mL). The resulting mixture wasstirred for 30 min and extracted twice with MTBE (10 mL each). Thecombined organic layers were washed with 30% aqueous NaCl (5.0 mL) anddried over MgSO₄. Filtration, concentration in vacuo, and purificationby silica gel column chromatography using a 10-33% gradient of ethylacetate in n-heptane as eluent provided 87 mg of the target product(compound 31). ¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm0.46-0.62 (m, 6H) 0.83-0.98 (m, 12H) 1.00 (s, 9H) 1.06 (s, 9H) 1.07-1.15(m, 6H) 1.25-2.04 (m, 19H) 2.08-2.24 (m., 2.5H) 2.32-2.44 (m, 1.5H)2.66-2.76 (m, 1H) 2.86-2.96 (m, 1H) 3.22-3.28 (m, 1H) 3.37-3.42 (m,0.5H) 3.46-3.71 (m, 6.5H) 3.73-3.86 (m, 4H) 3.93-4.00 (m, 4H) 4.05-4.23(m., 3H) 4.27-4.34 (m, 1H) 4.40-4.46 (m, 1H) 4.49 (q, J=6.4 Hz, 1H)4.58-4.68 (m, 1H) 4.70 (s, 1H) 4.76 (s, 1H) 4.84 (br. s., 1H) 4.90-5.14(m, 2H) 4.95-4.97 (m, 1H) 5.17 (d, J=10.6 Hz, 1H) 5.27 (dd, J=17.4, 1.8Hz, 1H) 5.59-5.70 (m, 1H) 5.73 (dd, J=15.6, 5.1 Hz, 1H) 5.80 (dd,J=15.6, 5.1 Hz, 1H) 5.84-5.97 (m, 1H) 7.27-7.43 (m, 24H) 7.55-7.79 (m,16H)

Compound 31 can be transformed into compound 3 according to thefollowing sequence:

Ring-Closing Olefin Metathesis

To a solution of(2S,3R,4S,4aS,6R,7R,8aS)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyloctahydropyrano[3,2-b]pyran-3-yl2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate(compound 31, 87 mg, 0.044 mmol) in toluene (61 mL) at 80° C. was addedquinone (4.8 mg, 0.044 mmol) and a solution of Hoveyda-Grubbs 2ndgeneration catalyst (5.59 mg, 8.891 μmol) in toluene (10 mL). Afterbeing stirred at 80° C. for 8 h, the reaction mixture was cooled toambient temperature and treated with DMSO (0.063 mL, 0.889 mmol). Theresulting solution was stirred overnight and concentrated in vacuo.Silica gel column chromatography of the residue using a 20-33% gradientof ethyl acetate in n-heptane as eluent afforded 71 mg of a mixture ofthe target product (compound 33a) and compound 32a: MS m/z 1908.0 and1936.0 [M+Na]⁺. The mixture was dissolved in THF (2.0 mL) at ambienttemperature. To the solution was added acetic acid (3.2 mL) and water(0.8 mL). After being stirred for 3 h at ambient temperature, theresulting mixture was concentrated in vacuo. The residue was purified bysilica gel column chromatography using a 10-33% gradient of ethylacetate in n-heptane as eluent to give 46 mg of a mixture of compound 33and compound 32. The mixture was dissolved in dichloromethane (45 mL)and treated with Hoveyda-Grubbs 2nd generation catalyst (2.91 mg, 4.63μmol) at reflux (45° C. oil bath) over 15 h. The reaction mixture wascooled to ambient temperature and concentrated in vacuo. Purification bysilica gel column chromatography of the residue using a 15-33% gradientof ethyl acetate in n-heptane as eluent afforded 15 mg of the targetproduct (compound 33). ¹H NMR (major isomer, 400 MHz, CDCl₃) δ ppm0.99-1.10 (m, 42H) 1.25-2.27 (m, 19H) 2.32-2.42 (m, J=7.4 Hz, 3H)2.45-2.51 (m, 1H) 2.55 (dd, J=14.9, 3.1 Hz, 1H) 2.69-2.79 (m, 1H) 2.85(t, J=9.0 Hz, 1H) 3.17-3.27 (m, 1H) 3.33-3.55 (m, 4H) 3.59-3.81 (m, 11H)3.87-3.95 (m, 1H) 4.15 (dd, J=8.6, 3.9 Hz, 1H) 4.29-4.39 (m, 2H)4.41-4.48 (m, 1H) 4.49-4.55 (m, 1H) 4.58-4.67 (m, 2H) 4.76 (s, 1H) 4.83(s, 1H) 4.92 (br. s., 2H) 5.77 (ddd, J=15.6, 7.6, 1.4 Hz, 1H) 6.31 (dd,J=15.4, 4.5 Hz, 1H) 7.30-7.43 (m, 24H) 7.58-7.77 (m, 16H)

(2S,3R,4S,4aS,6R,7R,8aS)-7-((tert-butyldiphenylsilyl)oxy)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyl-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5R)-3-methylene-5-vinyltetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)octahydropyrano[3,2-b]pyran-3-yl2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxybut-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

¹H NMR (compound 32, 400 MHz, CDCl₃) δ ppm 1.00-1.11 (m, 42H) 1.25-2.03(m, 19H) 2.12-2.22 (m, 2H) 2.33-2.42 (m, 2H) 2.72 (ddd, J=15.3, 6.7, 1.8Hz, 1H) 2.95 (dd, J=9.8, 4.3 Hz, 1H) 3.24 (dd, J=5.7, 3.7 Hz, 1H)3.47-3.56 (m, 3H) 3.59-3.69 (m, 5H) 3.72-3.80 (m, 3H) 3.81-3.88 (m, 1H)3.99-4.08 (m, 1H) 4.10-4.20 (m, 2H) 4.25 (dd, J=6.3, 4.3 Hz, 1H)4.41-4.50 (m, 2H) 4.67 (t, J=8.0 Hz, 1H) 4.72 (s, 1H) 4.78 (s, 1H) 4.85(d, J=2.0 Hz, 1H) 4.96 (d, J=2.0 Hz, 1H) 5.04 (d, J=10.2 Hz, 1H) 5.10(d, J=10.2 Hz, 1H) 5.16 (d, J=16.8 Hz, 1H) 5.23 (d, J=17.2 Hz, 1H) 5.72(ddd, J=16.9, 10.6, 6.1 Hz, 1H) 5.84 (ddd, J=17.0, 10.4, 6.3 Hz, 1H)7.27-7.45 (m, 24H) 7.56-7.78 (m, 16H)

Compound 37

Compound 33 (25.5 mg, 0.015 mmol) was dissolved in dichloromethane (1.0ml) at ambient temperature. Sodium bicarbonate (12.3 mg, 0.146 mmol) andDess-Martin periodinane (18.6 mg, 0.044 mmol) were added, and theresulting mixture was stirred at ambient temperature overnight. MTBE(10.0 ml), water (2.0 mL) and a saturated aqueous sodium thiosulfatesolution (5 mL) were added. The resulting mixture was stirred at ambienttemperature over 30 min. The organic layer was separated out, washedwith 30% aqueous NaCl (3.0 mL), and dried over MgSO₄. Filtration,concentration in vacuo, and purification by silica gel columnchromatography using a 10-33% gradient of ethyl acetate in n-heptane aseluent provided 17 mg of the target product (compound 37). ¹H NMR (400MHz, CDCl₃) δ ppm 0.97-1.17 (m, 42H) 1.28-2.25 (m, 20H) 2.49 (dd,J=16.0, 7.0 Hz, 1H) 2.56 (dd, J=15.0, 10.0 Hz, 1H) 2.72 (dd, J=15.2, 3.5Hz, 1H) 2.75-2.82 (m, 1H) 2.98 (t, J=8.8 Hz, 1H) 3.19-3.25 (m, 1H) 3.36(d, J=12.5 Hz, 1H) 3.42 (t, J=4.3 Hz, 1H) 3.48-3.57 (m, 4H) 3.60-3.70(m, 5H) 3.71-3.82 (m, 3H) 3.90 (td, J=10.4, 3.9 Hz, 1H) 4.01 (ddd,J=10.6, 7.4, 3.1 Hz, 1H) 4.08 (dd, J=8.0, 4.5 Hz, 1H) 4.24-4.35 (m, 2H)4.55-4.59 (m, 1H) 4.62 (t, J=7.4 Hz, 1H) 4.66-4.73 (m, 1H) 4.76 (s, 1H)4.85 (s, 1H) 4.91 (s, 1H) 5.00 (d, J=1.6 Hz, 1H) 6.41 (d, J=16.0 Hz, 1H)6.86 (dd, J=16.2, 5.7 Hz, 1H) 7.28-7.43 (m, 24H) 7.57-7.77 (m, 16H)

Compound 34

Compound 37 (4.0 mg, 2.3 μmol) was dissolved in deoxygenated toluene(0.6 mL) at ambient temperature. Deoxygenated (purged with nitrogen for40 min) water (2.4 μL, 0.13 mmol) was added followed byhydrido(triphenylphosphine)copper(I) hexamer (9.0 mg, 4.6 μmol). Afterbeing stirred for 1 h, the reaction mixture was treated with air.Copper-containing decomposition products precipitated. Concentration invacuo followed by purification by column chromatography using a 10-33%gradient of ethyl acetate in n-heptane as eluent afforded 3.0 mg of thetarget product (compound 34). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.98-1.14(m, 42H) 1.28-2.40 (m, 22H) 2.55-2.77 (m, 4H) 2.81-2.90 (m, 1H) 2.91 (t,J=9.2 Hz, 1H) 3.06 (t, J=11.7 Hz, 1H) 3.20 (dd, J=6.3, 3.9 Hz, 1H)3.39-3.47 (m, 2H) 3.50-3.57 (m, 2H) 3.62-3.69 (m, 3H) 3.72 (dd, J=6.1,4.5 Hz, 1H) 3.75-3.85 (m, 3H) 3.94-4.02 (m, 1H) 4.09 (dd, J=8.4, 3.7 Hz,2H) 4.26-4.32 (m, 1H) 4.33-4.39 (m, 1H) 4.43-4.48 (m, 1H) 4.64 (t, J=7.0Hz, 1H) 4.77 (s, 1H) 4.84 (s, 1H) 4.86 (s, 1H) 4.93 (s, 1H) 7.28-7.44(m, 24H) 7.57-7.77 (m, 16H)

Compound 3

To compound 34 (3.0 mg, 1.72 μmol) in a vial was added THF (0.6 mL) andN,N-dimethylacetamide (0.21 mL) at ambient temperature. A mixture ofTBAF (1.0 M in THF, 52 μL, 0.052 mmol) and imidazole hydrochloride (2.7mg, 0.026 mmol) was added, and the resulting mixture was stirred over 3days at ambient temperature. 30% aqueous NaCl (2.0 mL) was added, andthe resulting mixture was extracted twice with a mixture of THF (5.0 mL)and toluene (5.0 mL). The combined organic layers were concentrated witha stream of nitrogen. The residue was dissolved in dichloromethane (1.0mL) at ambient temperature, and PPTS (18 mg, 72 μmol) was added. Onceall starting material was consumed (2 h), the reaction mixture waspurified by silica gel column chromatography using a 0-10% gradient ofmethanol in ethyl acetate as eluent to give 0.9 mg of the target product(compound 3). The structure was confirmed by ¹H NMR comparison with thereported spectrum. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.10 (d, J=6.3 Hz, 3H)1.18 (d, J=7.8 Hz, 3H) 1.27-2.40 (m, 25H) 2.41 (dd, J=16.8, 2.7 Hz, 1H)2.53 (dd, J=17.2, 10.2 Hz, 1H) 2.76-2.86 (m, 1H) 2.90 (dd, J=9.8, 2.3Hz, 1H) 3.29 (s, 1H) 3.52-3.57 (m, 2H) 3.64 (d, J=10.9 Hz, 1H) 3.69-3.89(m, 5H) 4.04 (dd, J=6.3, 4.3 Hz, 1H) 4.10-4.15 (m, 1H) 4.18 (dd, J=6.4,4.5 Hz, 1H) 4.21-4.28 (m, 1H) 4.36 (d, J=11.7 Hz, 1H) 4.38-4.44 (m, 2H)4.50 (t, J=2.3 Hz, 1H) 4.58-4.62 (m, 1H) 4.68 (t, J=4.5 Hz, 1H) 4.80(br. s., 2H) 4.98 (br. s., 1H) 5.08 (s, 1H)

Example 6—C. 19-C.20 Macrocyclization Through Nozaki-Hiyama-KishiReaction

A halichondrin macrolide 3 can be prepared according to the belowsequence.

Compound 38 can be converted to compound 39 through theNozaki-Hiyama-Kishi reaction (e.g., with Cr(II) and Ni(II) salts).Compound 39 can give compound 40 through nucleophilic ring-closingsubstitution reaction. Compound 40 can be converted to compound 3 afterglobal deprotection (e.g., removal of silyl groups with a fluoridesource, such as TBAF).

Example 7—C.26-C.27 Macrocyclization Through Nozaki-Hiyama-KishiReaction

A halichondrin macrolide 3 can be prepared according to the belowsequence.

Compound 41 can be converted to compound 42 through theNozaki-Hiyama-Kishi reaction (e.g., with Cr(II) and Ni(II) salts) withsubsequent silylation of the formed hydroxyl by chlorotriethylsilane.Compound 42 can be subjected to Vasella fragmentation conditions toprovide 43. DDQ deprotection of the MPM-group and selective oxidation ofthe resulting allylic alcohol by manganese (11) oxide can provide 44.The remaining hydroxyl group can be reacted with methanesulfonylchloride to give compound 45. Global desilylation of 45 withtetrabutylammonium fluoride (TBAF) can form the compound 46 bynucleophilic displacement of the mesylate and conjugate addition of adeprotected alcohol to an enone. Compound 46 can be reacted with aBrønsted acid (e.g., PPTs) to afford compound 3.

Example 8—C. 14-C.38 Halichondrin Intermediate Through Allene-PrinsReaction

A halichondrin C.14-C.38 intermediate 53 can be prepared according tothe below sequence.

Compound 47 (Aicher et al. Tetrahedron Letters, 33:1549-1552, 1992) canbe converted to 48 in a three step process [(1) diisobutylaluminumhydride reduction to the aldehyde, (2) Acid catalyzed acetonidedeprotection and dimethylacetal formation and (3) benzoylation]. Theallene-Prins reaction between 48 and 49 can be achieved by treatmentwith boron trifluoride diethyl etherate and methoxyacetic acid toprovide 50. Allylic reduction of the methoxyacetate can be accomplishedusing tetrakis(triphenylphosphine)palladium(0) with formic acid andtriethylamine resulting in 51. Deprotection of the benzoate groups canbe achieved by treatment with magnesium methoxide to provide 52.Finally, treatment of 52 with tert-butyldimethylsilyl chloride canprovide the known C.14-C.38 halichondrin intermediate 53 (Aicher et al.J. Am. Chem. Soc., 114:3162-3164, 1992).

OTHER EMBODIMENTS

Various modifications and variations of the described compositions andmethods of the invention will be apparent to those skilled in the artwithout departing from the scope and spirit of the invention. Althoughthe invention has been described in connection with specificembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out theinvention that are obvious to those skilled in the art are intended tobe within the scope of the invention.

Other embodiments are in the claims.

1. A method of preparing a macrocyclic intermediate in the synthesis ofa halichondrin macrolide, said method comprising performing amacrocyclization reaction on a non-macrocyclic intermediate, saidmacrocyclization reaction producing said macrocyclic intermediate byforming C.2-C.3, C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27bond in the structure of the halichondrin macrolide.
 2. The method ofclaim 1, wherein said performing said macrocyclization reactioncomprises contacting said non-macrocyclic intermediate with an organicbase and a Lewis acid.
 3. The method of claim 2, wherein saidnon-macrocyclic intermediate is a compound of formula (IA):

or a salt or a tautomer thereof, wherein each R is independentlyoptionally substituted alkyl or optionally substituted aryl; each of Dand D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and wherein said macrocyclic intermediate in the synthesis of ahalichondrin macrolide is a compound of formula (IB):

or a salt or a tautomer thereof.
 4. The method of claim 3, wherein eachR is optionally substituted alkyl.
 5. The method of claim 3 or 4,wherein both P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal.
 6. The method of any one of claims 3 to5, wherein P₅ is a hydroxyl protecting group.
 7. The method of any oneof claims 3 to 6, wherein R₃ and R₄ combine to form a bond, and R₅ is H.8. The method of any one of claims 2 to 7, wherein said organic base isDBU or triethylamine.
 9. The method of any one of claims 2 to 8, whereinsaid Lewis acid is a salt of Li or Zn.
 10. The method of claim 1,wherein said performing said macrocyclization reaction comprisescontacting said non-macrocyclic intermediate with an olefin metathesiscatalyst.
 11. The method of claim 10, wherein said non-macrocyclicintermediate is a compound of formula (IIA):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and wherein said macrocyclic intermediate in the synthesis of ahalichondrin macrolide is a compound of formula (IB):

or a salt or a tautomer thereof.
 12. The method of claim 10, whereinsaid non-macrocyclic intermediate is a compound of formula (IIIA):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and wherein said macrocyclic intermediate in the synthesis of ahalichondrin macrolide is a compound of formula (IIIB):

or a salt or a tautomer thereof.
 13. The method of claim 11 or 12,wherein both P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal.
 14. The method of any one of claims 11to 13, wherein P₅ is a hydroxyl protecting group.
 15. The method ofclaim 10, said non-macrocyclic intermediate is a compound of formula(IVA):

or a salt thereof, wherein each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; (i) R₃ is H or a hydroxylprotecting group, R₄ is alkyl ether, and R₅ is H; (ii) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (iii) R₃ and R₄ combine to form a bond, and R₅ is H; each P₄ and P₅is independently H or a hydroxyl protecting group; R₆ is H, and P₆ is Hor a hydroxyl protecting group; or R₆ and P₆ combine to form a doublebond; and wherein said macrocyclic intermediate in the synthesis of ahalichondrin macrolide is a compound of formula (IVB):

or a salt thereof.
 16. The method of claim 15, wherein at least one ofP₄ and P₅ is H.
 17. The method of claim 10, wherein said non-macrocyclicintermediate is a compound of formula (VA):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; (a1) R₃ is H or a hydroxylprotecting group, R₄ is alkyl ether, and R₅ is H; (a2) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (a3) R₃ and R₄ combine to form a bond, and R₅ is H; (b1) A₁ and R₇combine to form oxo, R₆ is H or a hydroxyl protecting group, and R₈ isH; or (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting group,and: (i) R₆ is H or a hydroxyl protecting group, and R₇ and R₈ combineto form a double bond; or (ii) R₆ and R₇ combine to form a bond, and R₈is H or OP″; (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;or (c2) R₉ and P₄ combine to form a double bond; R₁₀ is H or—CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —C(R₁₁)₂—, or NP₆, and wherein eachR₁₁ is independently H or —COOR₁₂, P₆ is an N-protecting group, and R₁₂is alkyl; each P₅ is independently H or a hydroxyl protecting group; andwherein said macrocyclic intermediate in the synthesis of a halichondrinmacrolide is a compound of formula (VB):

or a salt or a tautomer thereof.
 18. The method of claim 17, wherein R₉is H, and P₄ is H.
 19. The method of claim 17 or 18, wherein R₁₀ is—CH₂X₁CH₂CH═CH₂, and X₁ is O.
 20. The method of any one of claims 17 to19, wherein R₆ and R₇ combine to form a bond, and R₈ is H.
 21. Themethod of any one of claims 15 to 20, wherein each P₅ is independently ahydroxyl protecting group.
 22. The method of any one of claims 15 to 20,wherein at least one P₅ is H.
 23. The method of any one of claims 15 to22, wherein R₃ and R₄ combine to form a bond, and R₅ is H.
 24. Themethod of any one of claims 10 to 23, wherein said olefin metathesiscatalyst is a ruthenium-carbene complex.
 25. The method of claim 1,wherein said performing said macrocyclization reaction comprisescontacting said non-macrocyclic intermediate with a Cr(II) salt and aNi(II) salt.
 26. The method of claim 25, wherein said non-macrocyclicintermediate is a compound of formula (VIA):

or a salt or a tautomer thereof, wherein Y is iodide, bromide, ortrifluoromethanesulfonate; b designates (R)-stereogenic center, and Z isa sulfonate, chloride, bromide, or iodide; or b designates(S)-stereogenic center, and Z is OR₆, wherein R₆ is a hydroxylprotecting group; each of D and D′ is independently H, optionallysubstituted alkyl, or OP₁, provided that only one of D and D′ is OP₁,wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is a group offormula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo; or bothP₄ groups and X₁, together with the atoms to which each is attached,combine to form ketal; and wherein said macrocyclic intermediate in thesynthesis of a halichondrin macrolide is a compound of formula (IVB):

or a salt or a tautomer thereof, wherein b designates (R)-stereogeniccenter, c designates (S)-stereogenic center, and Z is a sulfonate,chloride, bromide, or iodide; or b designates (S)-stereogenic center, cdesignates (R)-stereogenic center, and Z is OR₆, wherein R₆ is ahydroxyl protecting group.
 27. The method of claim 26, wherein Y isbromide.
 28. The method of claim 26 or 27, wherein R₃ and R₄ combine toform a bond, and R₅ is H.
 29. The method of any one of claims 26 to 28,wherein both P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal.
 30. The method of any one of claims 26to 29, wherein Z is a sulfonate.
 31. The method of any one of claims 26to 29, wherein Z is OR₆, wherein R₆ is a hydroxyl protecting group. 32.The method of claim 31, wherein Z is an ester, carbonate, or carbamate.33. The method of claim 25, wherein said non-macrocyclic intermediate isa compound of formula (VIIA):

or a salt thereof, wherein Y is iodide, bromide, ortrifluoromethanesulfonate; each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; (a1) R₃ is H or a hydroxylprotecting group, R₄ and R₅ combine to form a double bond, each P₄ isindependently H or a hydroxyl protecting group, and X₁, together withthe carbon to which it is attached, forms a carbonyl or —(CH(OR₈))—,wherein R₈ is H or a hydroxyl protecting group; or (a2) R₃ and R₄combine to form a bond, R₅ is H, and each P₄ is independently H or ahydroxyl protecting group, and X₁, together with the carbon to which itis attached, forms a carbonyl or —(CH(OR₈))—; or both P₄ groups and X₁,together with the atoms to which each is attached, combine to formketal; (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine toform a bond; or (b2) Z and R₇ combine to form a double bond, and R₆ is ahydroxyl protecting group; and wherein said macrocyclic intermediate inthe synthesis of a halichondrin macrolide is a compound of formula(VIIB):

or a salt thereof, wherein each of P₅ and R₆ is independently H or ahydroxyl protecting group.
 34. The method of claim 33, wherein Z isiodide.
 35. The method of claim 33 or 34, wherein Y istrifluoromethanesulfonate.
 36. The method of any one of claims 33 to 35,wherein R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine toform a double bond, each P₄ is independently H or a hydroxyl protectinggroup, and X₁, together with the carbon to which it is attached, forms—(CH(OR₈))—, wherein R₈ is H or a hydroxyl protecting group.
 37. Themethod of any one of claims 33 to 36, wherein at least one of P₃, P₄,and R₆ is a hydroxyl protecting group.
 38. The method of any one ofclaims 33 to 37, wherein Z is chloride, bromide, or iodide, and R₆ andR₇ combine to form a bond.
 39. A method of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (IB) from a compound of formula (IA),the compound of formula (IA) having the following structure:

or a salt or a tautomer thereof, wherein each R is independentlyoptionally substituted alkyl or optionally substituted aryl; A₁ and R₄combine to form oxo, R₃ is H or a hydroxyl protecting group, and R₅ isH; or A₁ is H or OP″, where P″ is H or a hydroxyl protecting group, and:(i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅ combine toform a double bond; or (ii) R₃ and R₄ combine to form a bond, and R₅ isH or OP″; each P₄ is independently H or a hydroxyl protecting group, andX₁ is oxo or X₁, together with the carbon atom to which it is attached,is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and the compound of formula (IB) having the following structure:

or a salt or a tautomer thereof; and (B) producing the halichondrinmacrolide from compound (IB).
 40. The method of claim 39, wherein saidproducing the compound of formula (IB) comprises reacting the compoundof formula (IA) with an organic base and a Lewis acid.
 41. The method ofclaim 39 or 40, wherein said producing the halichondrin macrolidecomprises reacting the compound of formula (IB) with a hydroxylprotecting group removing agent.
 42. The method of any one of claims 39to 41, wherein each R is optionally substituted alkyl.
 43. A method ofpreparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (IB) from a compound of formula (IIA),the compound of formula (IIA) having the following structure:

or a salt or a tautomer thereof, wherein A₁ and R₄ combine to form oxo,R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H or OP″,where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and The compound of formula (IB) having the following structure:

or a salt or a tautomer thereof; and (B) producing the halichondrinmacrolide from compound (IB).
 44. The method of claim 43, wherein saidproducing the compound of formula (IB) comprises reacting the compoundof formula (IIA) with an olefin metathesis catalyst.
 45. The method ofclaim 43 or 44, wherein said producing the halichondrin macrolidecomprises reacting the compound of formula (IB) with a hydroxylprotecting group removing agent.
 46. A method of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (IIIB) from a compound of formula(IIIA), the compound of formula (IIA) having the following structure:

or a salt or a tautomer thereof, wherein A₁ and R₄ combine to form oxo,R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H or OP″,where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup; and the compound of formula (IIIB) having the followingstructure:

or a salt or a tautomer thereof; and (B) producing the halichondrinmacrolide from the compound of formula (IIIB).
 47. The method of claim46, wherein said producing the compound of formula (IIIB) comprisesreacting the compound of formula (IIA) with an olefin metathesiscatalyst.
 48. The method of claim 46 or 47, wherein said producing thehalichondrin macrolide comprises reacting the compound of formula (IIIB)with a hydroxyl protecting group removing agent.
 49. The method of anyone of claims 39 to 48, wherein both P₄ groups and X₁, together with theatoms to which each is attached, combine to form ketal.
 50. The methodof any one of claims 39 to 49, wherein P₅ is a hydroxyl protectinggroup.
 51. A method of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R ad eP t combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (IVB) from a compound of formula (IVA),the compound of formula (IVA) having the following structure:

or a salt thereof, wherein (i) R₃ is H or a hydroxyl protecting group,R₄ is alkyl ether, and R₅ is H; (ii) R₃ is H or a hydroxyl protectinggroup, and R₄ and R₅ combine to form a double bond; or (iii) R₃ and R₄combine to form a bond, and R₅ is H; each P₄ and P₅ is independently Hor a hydroxyl protecting group; R₆ is H, and P₆ is H or a hydroxylprotecting group; or R₆ and P₆ combine to form a double bond; and thecompound of formula (IVB) having the following structure:

or a salt thereof; and (B) producing the halichondrin macrolide from thecompound of formula (IVB).
 52. The method of claim 51, wherein saidproducing the compound of formula (IVB) comprises reacting the compoundof formula (IVA) with an olefin metathesis catalyst.
 53. The method ofclaim 51 or 52, wherein said producing the halichondrin macrolide fromthe compound of formula (IVB) comprises reacting the compound of formula(IVB) with a Brønsted acid.
 54. The method of claim 51 or 52, whereinsaid producing the halichondrin macrolide comprises producing thecompound of formula (IVC), the compound of formula (IVC) having thefollowing structure:

or a salt thereof, wherein each of A₁ and A₂ is H or OP″, and wherein P″is H or a hydroxyl protecting group; and producing the halichondrinmacrolide from the compound of formula (IVC).
 55. The method of claim54, wherein said producing the compound of formula (IVC) comprisesreacting the compound of formula (IVB) with a hydroxyl protecting groupremoving agent.
 56. The method of claim 54 or 55, wherein said producingthe halichondrin macrolide from the compound of formula (IVC) comprisesreacting the compound of formula (IVC) with a Brønsted acid.
 57. Themethod of claim any one of claims 52 to 56, wherein at least one of P₄and P₅ is H.
 58. A method of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (VB) from a compound of formula (VA),the compound of formula (VA) having the following structure:

or a salt or a tautomer thereof, wherein (a1) R₃ is H or a hydroxylprotecting group, R₄ is alkyl ether, and R₅ is H; (a2) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (a3) R₃ and R₄ combine to form a bond, and R₅ is H; (b1) A₁ and R₇combine to form oxo, R₆ is H or a hydroxyl protecting group, and R₈ isH; or (b2) A₁ is H or OP″, where P″ is H or a hydroxyl protecting group,and: (i) R₆ is H or a hydroxyl protecting group, and R₇ and R₈ combineto form a double bond; or (ii) R₆ and R₇ combine to form a bond, and R₈is H or OP″; (c1) R₉ is H, and P₄ is H or a hydroxyl protecting group;or (c2) R₉ and P₄ combine to form a double bond; R₁₀ is H or—CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —C(R₁₁)₂—, or NP₆, and wherein eachR₁₁ is independently H or —COOR₁₂, P₆ is an N-protecting group, and R₁₂is alkyl; each P₅ is independently H or a hydroxyl protecting group; andwherein said macrocyclic intermediate in the synthesis of a halichondrinmacrolide is a compound of formula (VB):

or a salt or a tautomer thereof; (B) producing a compound of formula(VC) from the compound of formula (VB), the compound of formula (VC)having the following structure:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″;(C) producing a compound of formula (IVC) from the compound of formula(VC), the compound of formula (IVC) having the following structure:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″;and (D) producing the halichondrin macrolide from the compound offormula (IVC).
 59. The method of claim 58, wherein said producing thecompound of formula (VB) comprises contacting the compound of formula(VA) with an olefin metathesis catalyst.
 60. The method of claim 58 or59, wherein P₄ is H, R₉ is H, and said producing the compound of formula(VC) comprises oxidizing the compound of formula (VB) to produce acompound of formula (VBa):

or a salt thereof; and reacting the compound of formula (VBa) with a1,4-reducing agent to produce the compound of formula (VC).
 61. Themethod of any one of claims 58 to 60, wherein said producing thecompound of formula (IVC) comprises contacting the compound of formula(VC) with a hydroxyl protecting group removing agent.
 62. The method ofany one of claims 58 to 61, wherein said producing the halichondrinmacrolide comprises contacting the compound of formula (IVC) with aBrønsted acid.
 63. A method of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a 1-6saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (VIB) from a compound of formula (VIA),the compound of formula (VIA) having the following structure:

or a salt or a tautomer thereof, wherein Y is iodide, bromide, ortrifluoromethanesulfonate; b designates (R)-stereogenic center, and Z isa sulfonate, chloride, bromide, or iodide; or b designates(S)-stereogenic center, and Z is OR₆, wherein R₆ is a hydroxylprotecting group; A₁ and R₄ combine to form oxo, R₃ is H or a hydroxylprotecting group, and R₅ is H; or A₁ is H or OP″, where P″ is H or ahydroxyl protecting group, and: (i) R₃ is H or a hydroxyl protectinggroup, and R₄ and R₅ combine to form a double bond; or (ii) R₃ and R₄combine to form a bond, and R₅ is H or OP″; and each P₄ is independentlyH or a hydroxyl protecting group, and X₁ is oxo; or both P₄ groups andX₁, together with the atoms to which each is attached, combine to formketal; the compound of formula (VIB) having the following structure:

or a salt or a tautomer thereof, wherein b designates (R)-stereogeniccenter, c designates (S)-stereogenic center, and Z is a sulfonate,chloride, bromide, or iodide; or b designates (S)-stereogenic center, cdesignates (R)-stereogenic center, and Z is OR₆, wherein R₆ is ahydroxyl protecting group; (B) producing the halichondrin macrolide fromthe compound of formula (VIB).
 64. The method of claim 63, wherein saidproducing the compound of formula (VIB) comprises reacting the compoundof formula (VIA) with a Cr(II) salt and a Ni(II) salt.
 65. The method ofclaim 63 or 64, wherein said producing the halichondrin macrolidecomprises the step of nucleophilic ring-closing of the compound offormula (VIB).
 66. The method of any one of claims 63 to 65, whereinboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal.
 67. The method of any one of claims 39to 66, wherein R₃ and R₄ combine to form a bond, and R₅ is H.
 68. Amethod of preparing:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″,where each P″ is independently H or a hydroxyl protecting group; each ofD and D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; said method comprising: (A)producing a compound of formula (VIIB) from a compound of formula(VIIA), the compound of formula (VIIA) having the following structure:

or a salt thereof, wherein Y is iodide, bromide, ortrifluoromethanesulfonate; (a1) R₃ is H or a hydroxyl protecting group,R₄ and R₅ combine to form a double bond, each P₄ is independently H or ahydroxyl protecting group, and X₁, together with the carbon to which itis attached, forms a carbonyl or —(CH(OR₈))—; or (a2) R₃ and R₄ combineto form a bond, R₅ is H, and each P₄ is independently H or a hydroxylprotecting group, and X₁, together with the carbon to which it isattached, forms a carbonyl or —(CH(OR₈))—; or both P₄ groups and X₁,together with the atoms to which each is attached, combine to formketal; (b1) Z is chloride, bromide, or iodide, and R₆ and R₇ combine toform a bond; or (b2) Z and R₇ combine to form a double bond, and R₆ is ahydroxyl protecting group; and wherein R₈ is H or a hydroxyl protectinggroup the compound of formula (VIIB) having the following structure:

or a salt thereof, wherein each of P₅ and R₆ is H or a hydroxylprotecting group; (B) producing a compound of formula (VIIC) from thecompound of formula (VIIB), the compound of formula (VIIC) having thefollowing structure:

or a salt or a tautomer thereof, wherein A₁ and R₄ combine to form oxo,R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H or OP″,where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; (C)producing a compound of formula (VIID) from the compound of formula(VIIC), the compound of formula (VIID) having the following structure:

or a salt thereof, wherein each of A₁ and A₂ is independently H or OP″;and (D) producing the halichondrin macrolide from the compound offormula (VIID).
 69. The method of claim 68, wherein said producing thecompound of formula (VIIB) comprises reacting the compound of formula(VIIA) with a Cr(II) salt and a Ni(II) salt.
 70. The method of claim 68or 69, wherein said producing the compound of formula (VIIC) comprisesthe step of nucleophilic ring-closing of the compound of formula (VIIB).71. The method of any one of claims 68 to 70, wherein said producing thecompound of formula (VIID) comprises reacting the compound of formula(VIIC) with a hydroxyl protecting group removing agent.
 72. The methodof any one of claims 68 to 71, wherein said producing the halichondrinmacrolide comprises reacting the compound of formula (VIID) with aBrønsted acid.
 73. The method of any one of claims 68 to 72, wherein Zis iodide.
 74. The method of any one of claims 68 to 73, wherein Y istrifluoromethanesulfonate.
 75. The method of any one of claims 68 to 74,wherein R₃ is H or a hydroxyl protecting group, and R₄ and R₅ combine toform a double bond.
 76. The method of any one of claims 68 to 75,wherein each P₄ is independently H or a hydroxyl protecting group, andX₁, together with the carbon to which it is attached, forms —(CH(OR₈))—,wherein R₈ is H or a hydroxyl protecting group.
 77. The method of anyone of claims 68 to 76, wherein P₅ is H.
 78. The method of any one ofclaims 68 to 77, wherein Z is chloride, bromide, or iodide, and R₆ andR₇ combine to form a bond.
 79. The method of any one of claims 3-7,11-23, and 26-78, wherein a designates (S)-stereogenic center.
 80. Themethod of any one of claims 3-7, 11-23, and 26-79, wherein one and onlyone of D and D′ is optionally substituted alkyl or OP₁.
 81. The methodof claim 80, wherein one and only one of D and D′ is OP₁, wherein P₁ isH, alkyl, or a hydroxyl protecting group.
 82. The method of any one ofclaims 3-7, 11-23, and 26-81, wherein A is a group of formula (1). 83.The method of any one of claims 3-7, 11-23, and 26-82, wherein L is—(CH(OP₂))—.
 84. The method of any one of claims 3-7, 11-23, and 26-83,wherein R₁ and P₁ combine to form a bond.
 85. The method of any one ofclaims 3-7, 11-23, and 26-84, wherein G is O.
 86. The method of any oneof claims 3-7, 11-23, and 26-85, wherein E is optionally substitutedalkyl.
 87. The method of any one of claims 3-7, 11-23, and 26-86,wherein k is
 1. 88. The method of any one of claims 3-7, 11-23, and26-87, wherein R₂ is —(CH₂)_(n)OP₃.
 89. The method of any one of claims3-7, 11-23, and 26-88, wherein at least one of P₂ and P₃ is a hydroxylprotecting group.
 90. The method of any one of claims 3-7, 11-23, and26-89, wherein A₁ is H.
 91. A method of preparing an intermediate in thesynthesis of a halichondrin macrolide, said method comprising performingan allene-Prins reaction by contacting a compound of formula (VIIIA)with a compound of formula (VIIIB) and R₄OH, wherein R₄ is an optionallysubstituted acyl; wherein the compound of formula (VIIIA) has thefollowing structure:

or a salt thereof, wherein each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; X is O, or X, together withthe carbon atom to which it is attached, forms —(C(OP_(z))₂)—, whereineach P_(z) is independently optionally substituted alkyl or optionallysubstituted aryl, or both P_(z) combine to form optionally substitutedalkylene or optionally substituted arylene; and P₄ is H or a hydroxylprotecting group; wherein the compound of formula (VIIIB) has thefollowing structure:

wherein R₃ is —CH₂—OP₅, —CH═CH₂,

wherein P₅ is H or a hydroxyl protecting group; each P₆ is independentlya hydroxyl protecting group, or both P₆ groups, together with the atomsto which each is attached, combine to form a cyclic protected diol; andR₅ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —CH₂—, or NP₇, wherein P₇is a sulfonyl; and wherein said intermediate is a compound of formula(VIIIC):

or a salt thereof.
 92. The method of claim 91, wherein said performing aPrins reaction comprises reacting the compound of formula (VIIIA) with aLewis acid.
 93. The method of claim 91 or 92, wherein k is
 1. 94. Acompound of formula (IA) or formula (IB),

or a salt or a tautomer thereof, wherein each R is independentlyoptionally substituted alkyl or optionally substituted aryl; each of Dand D′ is independently H, optionally substituted alkyl, or OP₁,provided that only one of D and D′ is OP₁, wherein P₁ is H, alkyl, or ahydroxyl protecting group; A is a group of formula (1) or a C₁₋₆saturated or C₂₋₆ unsaturated hydrocarbon skeleton, the skeleton beingunsubstituted or having from 1 to 10 substituents independently selectedfrom the group consisting of cyano, halo, azido, oxo, and Q₁, the groupof formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup.
 94. A compound of formula (IIA), formula (IIIA), or formula(IIIB):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄ combine to formoxo, R₃ is H or a hydroxyl protecting group, and R₅ is H; or A₁ is H orOP″, where P″ is H or a hydroxyl protecting group, and: (i) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (ii) R₃ and R₄ combine to form a bond, and R₅ is H or OP″; each P₄ isindependently H or a hydroxyl protecting group, and X₁ is oxo or X₁,together with the carbon atom to which it is attached, is—(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; and P₅ is H or a hydroxyl protectinggroup.
 95. A compound of formula (IVA), formula (IVB), or formula (IVC):

or a salt thereof, wherein each of A₁ and A₂ is H or OP″, where P″ is Hor a hydroxyl protecting group; each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; (i) R₃ is H or a hydroxylprotecting group, R₄ is alkyl ether, and R₅ is H; (ii) R₃ is H or ahydroxyl protecting group, and R₄ and R₅ combine to form a double bond;or (iii) R₃ and R₄ combine to form a bond, and R₅ is H; each P₄ and P₅is independently H or a hydroxyl protecting group; and R₆ is H, and P₆is H or a hydroxyl protecting group; or R₆ and P₆ combine to form adouble bond.
 96. A compound of formula (VA), formula (VB), or formula(VC):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; A₂is H or OP″; E is optionally substituted alkyl or optionally substitutedalkoxy; G is O, S, CH₂, or NR_(N), wherein R_(N) is H, an N-protectinggroup, or optionally substituted alkyl; each Q₁ is independently OR_(A),SR_(A), SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A),NR_(B)(CO)(CO)R_(A), NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A),(CO)OR_(A), O(CO)R_(A), (CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), whereineach of R_(A) and R_(B) is independently H, alkyl, haloalkyl,hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl,arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl,heterocyclic radical, or heterocyclic radical-alkyl; k is 0 or 1; n is0, 1, or 2; (a1) R₃ is H or a hydroxyl protecting group, R₄ is alkylether, and R₅ is H; (a2) R₃ is H or a hydroxyl protecting group, and R₄and R₅ combine to form a double bond; or (a3) R₃ and R₄ combine to forma bond, and R₅ is H; (b1) A₁ and R₇ combine to form oxo, R₆ is H or ahydroxyl protecting group, and R₈ is H; or (b2) A₁ is H or OP″, where P″is H or a hydroxyl protecting group, and: (i) R₆ is H or a hydroxylprotecting group, and R₇ and R₈ combine to form a double bond; or (ii)R₆ and R₇ combine to form a bond, and R₈ is H or OP″; (c1) R₉ is H, andP₄ is H or a hydroxyl protecting group; or (c2) R₉ and P₄ combine toform a double bond; R₁₀ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O,—C(R₁₁)₂—, or NP₆, and wherein each R₁₁ is independently H or —COOR₁₂,P₆ is an N-protecting group, and R₁₂ is alkyl; each P₅ is independentlyH or a hydroxyl protecting group; and
 97. A compound of formula (VIA):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; Y is iodide, bromide, ortrifluoromethanesulfonate; b designates (R)-stereogenic center, and Z isa sulfonate, chloride, bromide, or iodide; or b designates(S)-stereogenic center, and Z is OR₆, wherein R₆ is a hydroxylprotecting group; A₁ and R₄ combine to form oxo, R₃ is H or a hydroxylprotecting group, and R₅ is H; or A₁ is H or OP″, where P″ is H or ahydroxyl protecting group, and: (i) R₃ is H or a hydroxyl protectinggroup, and R₄ and R₅ combine to form a double bond; or (ii) R₃ and R₄combine to form a bond, and R₅ is H or OP″; each P₄ is independently Hor a hydroxyl protecting group, and X₁ is oxo or X₁, together with thecarbon atom to which it is attached, is —(CH(OP_(Y)))—, wherein P_(Y) isH or a hydroxyl protecting group; or both P₄ groups and X₁, togetherwith the atoms to which each is attached, combine to form ketal.
 98. Acompound of formula (VIB):

or a salt or a tautomer thereof, wherein b designates (R)-stereogeniccenter, c designates (S)-stereogenic center, and Z is a sulfonate,chloride, bromide, or iodide; or b designates (S)-stereogenic center, cdesignates (R)-stereogenic center, and Z is OR₆, wherein R₆ is ahydroxyl protecting group; each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; k is 0 or 1; n is 0, 1, or 2; A₁ and R₄combine to form oxo, R₃ is H or a hydroxyl protecting group, and R₅ isH; or A₁ is H or OP″, where P″ is H or a hydroxyl protecting group, and:(i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅ combine toform a double bond; or (ii) R₃ and R₄ combine to form a bond, and R₅ isH or OP″; each P₄ is independently H or a hydroxyl protecting group, andX₁ is oxo or X₁, together with the carbon atom to which it is attached,is —(CH(OP_(Y)))—, wherein P_(Y) is H or a hydroxyl protecting group; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal.
 99. A compound of formula (VIIA) orformula (VIIB):

or a salt thereof, wherein each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; (a1) R₃ is H or a hydroxylprotecting group, R₄ and R₅ combine to form a double bond, each P₄ isindependently H or a hydroxyl protecting group, and X₁, together withthe carbon to which it is attached, forms a carbonyl or —(CH(OR₈))—; or(a2) R₃ and R₄ combine to form a bond, R₅ is H, and each P₄ isindependently H or a hydroxyl protecting group, and X₁, together withthe carbon to which it is attached, forms a carbonyl or —(CH(OR₈))—; orboth P₄ groups and X₁, together with the atoms to which each isattached, combine to form ketal; (b1) Z is chloride, bromide, or iodide,and R₆ and R₇ combine to form a bond; (b2) Z and R₇ combine to form adouble bond, and R₆ is a hydroxyl protecting group; or (b3) when Z andR₇ are absent, R₆ is H or a hydroxyl protecting group; P₅ is H or ahydroxyl protecting group; wherein R₈ is H or a hydroxyl protectinggroup.
 100. A compound of formula (VIIC):

or a salt or a tautomer thereof, wherein each of D and D′ isindependently H, optionally substituted alkyl, or OP₁, provided thatonly one of D and D′ is OP₁, wherein P₁ is H, alkyl, or a hydroxylprotecting group; A is a group of formula (1) or a C₁₋₆ saturated orC₂₋₆ unsaturated hydrocarbon skeleton, the skeleton being unsubstitutedor having from 1 to 10 substituents independently selected from thegroup consisting of cyano, halo, azido, oxo, and Q₁, the group offormula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

 wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is 0 or 1; n is 0, 1, or 2; each P₄ is H or a hydroxylprotecting group, and X₁ is oxo or X₁, together with the carbon atom towhich it is attached, is —(CH(OP_(Y)))—, wherein P_(Y) is H or ahydroxyl protecting group; or both P₄ groups and X₁, together with theatoms to which each is attached, combine to form a ketal; and A₁ and R₄combine to form oxo, R₃ is H or a hydroxyl protecting group, and R₅ isH; or A₁ is H or OP″, where P″ is H or a hydroxyl protecting group, and:(i) R₃ is H or a hydroxyl protecting group, and R₄ and R₅ combine toform a double bond; or (ii) R₃ and R₄ combine to form a bond, and R₅ isH or OP″.
 101. A compound of formula (VIIIC):

or a salt thereof, wherein each of D and D′ is independently H,optionally substituted alkyl, or OP₁, provided that only one of D and D′is OP₁, wherein P₁ is H, alkyl, or a hydroxyl protecting group; A is agroup of formula (1) or a C₁₋₆ saturated or C₂₋₆ unsaturated hydrocarbonskeleton, the skeleton being unsubstituted or having from 1 to 10substituents independently selected from the group consisting of cyano,halo, azido, oxo, and Q₁, the group of formula (1) having the structure:

wherein L is —(CH(OP₂))—, —(C(OH)(OP₂))—, or —C(O)—; R₁ is H, or R₁ andP₁ combine to form a bond; R₂ is H or —(CH₂)_(n)OP₃, and each of P₂ andP₃ is independently H, optionally substituted alkyl, or a hydroxylprotecting group, or P₂ and P₃, together with the atoms to which each isattached, combine to form a ketal, a cyclic carbonate, adicarbonyl-dioxo, or silylene-dioxo; or R₂ and P₂ combine to form anoptionally substituted ethylene or a structure selected from the groupconsisting of:

wherein each P′ is independently H or a hydroxyl protecting group; E isoptionally substituted alkyl or optionally substituted alkoxy; G is O,S, CH₂, or NR_(N), wherein R_(N) is H, an N-protecting group, oroptionally substituted alkyl; each Q₁ is independently OR_(A), SR_(A),SO₂R_(A), OSO₂R_(A), NR_(B)R_(A), NR_(B)(CO)R_(A), NR_(B)(CO)(CO)R_(A),NR_(A)(CO)NR_(B)R_(A), NR_(B)(CO)OR_(A), (CO)OR_(A), O(CO)R_(A),(CO)NR_(B)R_(A), or O(CO)NR_(B)R_(A), wherein each of R_(A) and R_(B) isindependently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl,haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl,alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclicradical-alkyl; k is O or 1; n is 0, 1, or 2; P₄ is H or a hydroxylprotecting group; and R₃ is —CH₂—OP₅, —CH═CH₂,

wherein P₅ is H or a hydroxyl protecting group; each P₆ is independentlya hydroxyl protecting group, or both P₆ groups, together with the atomsto which each is attached, combine to form a cyclic protected diol; andR₅ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —CH₂—, or NP₇, wherein P₇is a sulfonyl.